{"gene":"CDC5L","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2000,"finding":"CDC5L is part of a larger multiprotein complex in HeLa nuclear extract that incorporates into the spliceosome in an ATP-dependent step and is required for the second catalytic step of pre-mRNA splicing. Immunodepletion of the CDC5L complex inhibits pre-mRNA splicing product formation in vitro but does not prevent spliceosome assembly; the purified complex restores splicing activity when added back to immunodepleted extracts.","method":"Immunodepletion from HeLa nuclear extract, in vitro splicing assay, mass spectrometry identification of complex components","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with immunodepletion/add-back, multiple orthogonal methods (in vitro splicing, MS), single lab with rigorous controls","pmids":["11101529"],"is_preprint":false},{"year":2001,"finding":"CDC5L directly interacts with PLRG1 via the carboxyl-terminal region of CDC5L and the WD40 domain of PLRG1; disruption of this interaction by a bacterially expressed competing peptide inhibits pre-mRNA splicing in HeLa nuclear extract, demonstrating that this protein-protein interaction is essential for pre-mRNA splicing.","method":"Co-immunoprecipitation in vivo, direct in vitro binding assay, competitive peptide disruption with in vitro splicing assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution of interaction, functional disruption with competing peptide in splicing assay, multiple orthogonal methods","pmids":["11544257"],"is_preprint":false},{"year":2010,"finding":"The human Prp19/CDC5L complex contains four copies of hPrp19, with a stable core comprised of CDC5L, hPrp19, PRL1, and SPF27. SPF27 directly interacts with each core component; limited proteolysis revealed a protease-resistant sub-complex of SPF27, the C-terminus of CDC5L, and N-termini of PRL1 and hPrp19. Under EM the complex has an elongated asymmetric shape (~20 nm).","method":"Native complex purification from HeLa cells, stoichiometric analysis, salt-treatment dissection, protein-protein interaction studies, limited proteolysis, electron microscopy","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural/biochemical characterization with multiple orthogonal methods (EM, proteolysis, stoichiometry, interaction mapping) in a single rigorous study","pmids":["20176811"],"is_preprint":false},{"year":2000,"finding":"NIPP1, a regulatory subunit of protein phosphatase-1, interacts with CDC5L through its FHA (forkhead-associated) domain in a phosphorylation-dependent manner; CDC5L is phosphorylated by cyclin E-Cdk2, which is required for the NIPP1 FHA domain to bind CDC5L. CDC5L, NIPP1, and PP1 form a complex in rat liver nuclear extracts. Expression of the NIPP1 FHA domain in cells blocks beta-globin pre-mRNA splicing, and a mutation that abolishes FHA-CDC5L interaction also abolishes this anti-splicing effect.","method":"Yeast two-hybrid, co-immunoprecipitation, co-purification from nuclear extracts, in vitro splicing assay, FHA domain mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, functional splicing assay with mutagenesis, phosphorylation dependency demonstrated, multiple orthogonal methods","pmids":["10827081"],"is_preprint":false},{"year":1999,"finding":"CDC5 (mammalian) colocalizes with pre-mRNA splicing factors in mammalian nuclei, associates with core spliceosomal components in nuclear extracts, and interacts with the spliceosome throughout the splicing reaction in vitro. Genetic depletion of the yeast homolog CEF1 blocks the first step of pre-mRNA processing in vivo.","method":"Immunofluorescence colocalization, nuclear extract co-immunoprecipitation, in vitro spliceosome assembly, yeast genetic depletion","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (colocalization, co-IP, in vitro splicing, genetics), independently corroborated across organisms","pmids":["10570151"],"is_preprint":false},{"year":2009,"finding":"CDC5L physically interacts with the checkpoint kinase ATR; depletion of CDC5L by RNAi causes a defective S-phase cell-cycle checkpoint and cellular sensitivity to replication-fork blocking agents. CDC5L is required for activation of downstream ATR effectors Chk1, Rad17, and FancD2. A CDC5L deletion mutant unable to bind ATR fails to rescue the checkpoint deficiency in CDC5L-depleted cells.","method":"Co-immunoprecipitation, RNAi knockdown, checkpoint assays (Chk1/Rad17/FancD2 phosphorylation), domain-mapping with deletion mutant rescue","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, domain-mapping rescue experiment, multiple downstream effector readouts, single lab with multiple orthogonal methods","pmids":["19633697"],"is_preprint":false},{"year":2008,"finding":"Cell cycle-dependent phosphorylation of human CDC5L at threonines 411 and 438 (within CDK recognition sequences) is required for CDC5L-mediated pre-mRNA splicing in vitro. CDK2 phosphorylates CDC5L in vitro and in vivo; a specific CDK2 inhibitor (CVT-313) inhibits CDC5L phosphorylation. CDC5L forms homodimers in vitro and in vivo, but homodimerization and nuclear localization do not depend on phosphorylation at these sites.","method":"2D phosphopeptide mapping, nanoelectrospray mass spectrometry, in vitro splicing assay with phosphorylation-site mutants, in vitro kinase assay, in vivo radiolabeling","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, in vitro splicing functional assay, MS site identification, single lab with multiple orthogonal methods","pmids":["18583928"],"is_preprint":false},{"year":1998,"finding":"Human CDC5 (hCdc5/CDC5L) promotes G2/M progression in mammalian cells: overexpression shortened G2 and reduced cell size, while a dominant-negative mutant lacking the C-terminal activation domain slowed G2 progression and delayed mitotic entry.","method":"Overexpression and dominant-negative mutant analysis in mammalian cells, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression/dominant-negative with cell cycle readout, no pathway mechanistic placement; replicated concept in multiple studies","pmids":["9468527"],"is_preprint":false},{"year":2000,"finding":"Human CDC5 binds specifically and with high affinity to a 12 bp DNA sequence through its amino terminus, and this DNA-protein interaction is capable of activating transcription. Multiple human genomic sequences with similar motifs also interact with CDC5.","method":"DNA binding assay, transcriptional activation assay, yeast selection system for genomic binding sites","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro DNA binding and transcription activation, single lab, single study","pmids":["11082045"],"is_preprint":false},{"year":2010,"finding":"hnRNP-M directly interacts with CDC5L and PLRG1 in vivo; this interaction is inhibited during heat-shock stress. A central region of hnRNP-M is required for CDC5L/PLRG1 interaction, and an hnRNP-M mutant lacking this domain is unable to modulate alternative splicing of an adeno-E1A mini-gene substrate.","method":"In vivo interaction assays, domain-mapping with truncation mutants, in vitro/in vivo alternative splicing assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction demonstrated in vivo, domain mapping, functional splicing assay with mutant, single lab","pmids":["20467437"],"is_preprint":false},{"year":2011,"finding":"CTNNBL1 binds the nuclear localization sequence (NLS) of CDC5L via its armadillo domain, mediating CTNNBL1 association with the Prp19 spliceosomal complex. CTNNBL1 also interacts with Prp31 through its NLS, but via a binding specificity distinct from karyopherin α.","method":"Co-immunoprecipitation, domain-mapping, NLS-binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and binding assays with domain mapping, single lab, multiple interaction partners characterized","pmids":["21385873"],"is_preprint":false},{"year":2015,"finding":"CTNNBL1 enhances the association of CWC15 with CDC5L in vitro; in vivo, CTNNBL1 deficiency reduces normal levels of the Prp19 complex and impairs CWC15-CDC5L interaction. The region of CDC5L that binds CTNNBL1 overlaps with that which binds CWC15, suggesting the two proteins may exchange at the complex. CTNNBL1 thus has a chaperone function required for Prp19 complex integrity.","method":"Amine crosslinking + hydrogen-deuterium exchange MS, in vitro binding assays, in vivo complex abundance analysis, CTNNBL1-deficient cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural MS approaches plus in vitro and in vivo functional assays, single lab","pmids":["26130721"],"is_preprint":false},{"year":2003,"finding":"Peptides derived from the CDC5L-PLRG1 binding interface inhibit pre-mRNA splicing in vitro; this inhibition is prevented by pre-incubating peptides with the corresponding partner protein, confirming that the direct CDC5L-PLRG1 interaction is mechanistically essential for splicing.","method":"Competitive peptide inhibition in in vitro splicing assay, rescue by recombinant partner protein","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution/competition assay with functional readout, single lab, single method","pmids":["14576297"],"is_preprint":false},{"year":2002,"finding":"DAP-like kinase (Dlk/ZIP kinase) interacts with rat CDC5 (homolog of human CDC5L) in vitro, but does not phosphorylate it directly; instead, an associated kinase identified as CK2 phosphorylates CDC5. Both proteins co-localize in nuclear speckles in vivo. The interaction domain of Dlk maps to its leucine zipper, and that of CDC5 maps to its C-terminal region (residues 500-802).","method":"In vitro binding assay, in vitro kinase assay, immunofluorescence colocalization, domain mapping","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding and kinase assays with domain mapping, colocalization, single lab","pmids":["11884640"],"is_preprint":false},{"year":2003,"finding":"hLodestar/HuF2 (SNF2 family) interacts with CDC5L in yeast two-hybrid and HeLa nuclear extracts; a truncated hLodestar/HuF2 polypeptide overlapping the CDC5L-binding region inhibits pre-mRNA splicing by disrupting spliceosome assembly.","method":"Yeast two-hybrid, co-immunoprecipitation from HeLa nuclear extract, in vitro splicing inhibition assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-IP plus functional splicing assay, single lab","pmids":["12927788"],"is_preprint":false},{"year":2012,"finding":"Alleles of yeast CEF1 (the S. cerevisiae ortholog of CDC5L) suppress second-step splicing defects caused by intron mutations, U6 snRNA mutations, or deletion of the second-step factor Prp17, and can activate alternative 3' splice sites. Genetic interactions with prp8 alleles suggest CEF1/CDC5L modulates the first-to-second-step conformational transition of the spliceosome, likely through its Myb-like domain.","method":"Genetic suppressor analysis, in vitro splicing assays with mutant alleles, epistasis with prp8 and U6 alleles","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple allele combinations, in vitro splicing assays, single lab","pmids":["22408182"],"is_preprint":false},{"year":2014,"finding":"The N-terminus of S. pombe Cdc5 (CDC5L ortholog) contains two canonical Myb repeats (R1, R2) and a third domain (D3) that, while not adopting a canonical Myb fold, preferentially binds double-stranded RNA in vitro. All three domains (R1, R2, D3) are required for Cdc5 function in yeast cells.","method":"Yeast genetics (truncation mutants), NMR/structural analysis of D3, RNA binding assays (EMSA), functional complementation","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural characterization plus RNA binding assays plus in vivo genetic functional assays, single lab","pmids":["25263959"],"is_preprint":false},{"year":2010,"finding":"Akt phosphorylates PRP19α at Thr193, which is critical for PRP19α binding to 14-3-3β; this allows nuclear translocation and formation of a PRP19α/14-3-3β/CDC5L complex required for active spliceosome assembly during NGF-induced neuronal differentiation of PC12 cells. A nonphosphorylatable PRP19α T193A mutant loses 14-3-3β binding and acts as a dominant negative in neuronal differentiation.","method":"Co-immunoprecipitation, dominant-negative mutant analysis, knockdown/overexpression in PC12 cells, nuclear fractionation","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, mutagenesis (T193A), dominant-negative rescue, single lab with multiple approaches","pmids":["20629186"],"is_preprint":false},{"year":2003,"finding":"Human CDC5 (CDC5L) nuclear import is directed by the amino-terminal domain independent of consensus nuclear localization signals or phosphorylation, while the carboxyl-terminus preferentially associates with spliceosomal complexes near RNA transcription sites during interphase. CDC5L colocalizes with Sm proteins in a cell cycle- and domain-dependent manner.","method":"Domain-deletion constructs, nuclear fractionation, immunofluorescence colocalization, cell cycle analysis","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain-deletion localization experiments with multiple markers, single lab","pmids":["14515018"],"is_preprint":false},{"year":2014,"finding":"Depletion of CDC5L causes dramatic mitotic arrest, chromosome misalignments, sustained spindle assembly checkpoint activation, severe impairment of kinetochore-microtubule attachment, and DNA damage, ultimately leading to mitotic catastrophe. Genome-wide expression analysis reveals that CDC5L modulates expression of mitosis and DNA damage response genes, and pre-mRNA splicing efficiency of these genes is impaired upon CDC5L knockdown.","method":"RNAi knockdown, live-cell imaging, chromosome spread analysis, genome-wide expression profiling, splicing efficiency assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with defined mitotic phenotype and splicing mechanism, multiple readouts, single lab","pmids":["24675469"],"is_preprint":false},{"year":2021,"finding":"Cdc5l (CDC5L) promotes early chondrogenesis and chondrocyte proliferation by modulating pre-mRNA splicing of Sox9, Col2a1, and Wee1. Knockdown of Cdc5l in murine chondrocytes decreased Sox9 and Col2a1 expression, enhanced Wee1 expression (causing G2/M arrest), and reduced pre-mRNA splicing efficiency of Sox9 and Col2a1 while paradoxically enhancing splicing of Wee1 pre-mRNA. RNA-binding protein immunoprecipitation confirmed direct binding of Cdc5l to these target transcripts.","method":"siRNA knockdown, FACS cell cycle analysis, cartilage rudiment culture, RNA-binding protein immunoprecipitation (RIP), splicing efficiency assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi + RIP confirming direct RNA binding + splicing assays + cell cycle phenotype, single lab with multiple orthogonal methods","pmids":["34298017"],"is_preprint":false},{"year":1998,"finding":"The human CDC5L gene maps to chromosome 6p21, consists of at least 16 exons spanning ~50 kb, and encodes a ~100 kDa nuclear protein. Immunocytochemistry confirmed nuclear localization. The protein contains a Myb-related DNA binding domain and nuclear localization signals in its N-terminus and a proline-rich putative transcriptional activating domain in its central region.","method":"Genomic organization mapping, immunocytochemistry, Western blot, Northern blot","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by immunocytochemistry, genomic characterization only; no direct functional experiment beyond confirming nuclear localization","pmids":["9598309"],"is_preprint":false},{"year":1997,"finding":"Human CDC5L (PCDC5RP) translocates rapidly from cytoplasm to nucleus upon serum stimulation of cultured cells, correlating temporally with increased CDC5L phosphorylation, suggesting it transduces cytoplasmic signals to the nucleus.","method":"Immunofluorescence, subcellular fractionation, phosphorylation analysis after serum stimulation","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization observation with phosphorylation correlation, no mechanistic follow-up, single study","pmids":["9038199"],"is_preprint":false},{"year":2017,"finding":"CDC5L binds directly to the hTERT promoter (identified by pulldown with biotin-labeled hTERT promoter and confirmed by ChIP assay) and acts as a transcriptional activator of hTERT, as shown by luciferase reporter assay. CDC5L knockdown inhibits tumor growth by down-regulating hTERT expression.","method":"Biotin-labeled DNA pulldown, ChIP assay, luciferase reporter assay, siRNA knockdown","journal":"Cellular physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ChIP and reporter assay with limited mechanistic depth","pmids":["28472785"],"is_preprint":false},{"year":2020,"finding":"CDC5L protein binds directly to the PEAK1 gene promoter to promote its transcription, as confirmed by chromatin immunoprecipitation (ChIP) assay in ovarian cancer cells.","method":"ChIP assay, transcriptional reporter, siRNA knockdown","journal":"Cancer medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP assay for direct promoter binding, single lab, cancer-cell context only","pmids":["32167655"],"is_preprint":false},{"year":2017,"finding":"Prp19 regulates CDC5L protein levels post-transcriptionally: silencing Prp19 in HCC cells inhibits Cdc5L mRNA translation and facilitates lysosome-mediated degradation of CDC5L protein. Overexpression of CDC5L partially rescues the cell cycle arrest caused by Prp19 knockdown, placing Prp19 upstream of CDC5L in the mitotic progression pathway.","method":"siRNA knockdown, overexpression rescue, lysosomal inhibitor experiments, Western blot, flow cytometry","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanism inferred from rescue and inhibitor experiments without direct biochemical reconstitution","pmids":["28387715"],"is_preprint":false},{"year":2024,"finding":"IGF2BP1, an m6A reader, binds to m6A sites on CDC5L mRNA and up-regulates CDC5L protein abundance post-transcriptionally. Knockdown or mutation of CDC5L attenuates the pro-proliferative effect of IGF2BP1 in multiple myeloma cells with chromosome 1q gain.","method":"m6A sequencing, RIP assay, siRNA knockdown, mutant analysis, in vitro and in vivo proliferation assays","journal":"Genes & diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanism is post-transcriptional regulation of CDC5L mRNA by m6A reader; RIP and functional rescue but limited mechanistic depth on CDC5L itself","pmids":["39534570"],"is_preprint":false}],"current_model":"CDC5L (human CDC5/hCDC5/PCDC5RP) is a core component of the Prp19/CDC5L spliceosomal complex required for the second catalytic step of pre-mRNA splicing; it directly interacts with PLRG1 (via its C-terminal domain binding the PLRG1 WD40 domain), with CTNNBL1 (via its NLS), and with the spliceosome throughout the splicing reaction, while its splicing activity is regulated by CDK2-mediated phosphorylation at T411/T438. Beyond splicing, CDC5L interacts with the checkpoint kinase ATR and is required for ATR-mediated S-phase checkpoint activation (including Chk1, Rad17, and FancD2 phosphorylation); it also functions as a site-specific DNA-binding and transcriptional activator through its N-terminal Myb repeats, can promote G2/M progression when overexpressed, and regulates the splicing of chondrogenic genes (SOX9, COL2A1, WEE1) in chondrocytes."},"narrative":{"mechanistic_narrative":"CDC5L is a core component of the human Prp19/CDC5L spliceosomal complex and is required for the second catalytic step of pre-mRNA splicing; it incorporates into the spliceosome in an ATP-dependent step and associates with the spliceosome throughout the reaction, with immunodepletion blocking splicing product formation without preventing spliceosome assembly [PMID:11101529, PMID:10570151]. Within the complex it forms a stable core with hPrp19, PRL1, and SPF27, in which SPF27 contacts each core subunit and a protease-resistant subcomplex includes the C-terminus of CDC5L [PMID:20176811]. CDC5L makes a direct, splicing-essential interaction with PLRG1 through its C-terminal region binding the PLRG1 WD40 domain, and competing peptides that disrupt this interface abolish splicing in vitro [PMID:11544257, PMID:14576297]. Its incorporation and complex integrity are mediated by CTNNBL1, which binds the CDC5L nuclear localization sequence via its armadillo domain and functions as a chaperone that supports CWC15-CDC5L association and overall Prp19 complex levels [PMID:21385873, PMID:26130721]. Splicing activity is gated by cell-cycle phosphorylation: CDK2 phosphorylates CDC5L at T411/T438, an event required for splicing, while NIPP1/PP1 docks onto cyclin E-Cdk2-phosphorylated CDC5L through its FHA domain [PMID:18583928, PMID:10827081]. Beyond splicing, CDC5L physically associates with the checkpoint kinase ATR and is required for ATR-dependent S-phase checkpoint signaling, including phosphorylation of Chk1, Rad17, and FancD2 [PMID:19633697]. Loss of CDC5L causes mitotic catastrophe with chromosome misalignment, impaired kinetochore-microtubule attachment, and defective splicing of mitosis and DNA-damage-response genes [PMID:24675469], and in chondrocytes CDC5L directly binds and regulates splicing of SOX9, COL2A1, and WEE1 to drive chondrogenesis [PMID:34298017]. The N-terminal Myb-like repeats confer site-specific DNA binding and transcriptional activation activity [PMID:11082045].","teleology":[{"year":1998,"claim":"Established CDC5L as a nuclear ~100 kDa protein with N-terminal Myb-related DNA-binding domain and a central proline-rich activation domain, and showed overexpression promotes G2/M progression — first hint of a cell-cycle role.","evidence":"Genomic organization mapping and overexpression/dominant-negative cell-cycle analysis in mammalian cells","pmids":["9598309","9468527"],"confidence":"Medium","gaps":["G2/M effect inferred from over/under-expression without endogenous pathway placement","Molecular function (splicing) not yet defined"]},{"year":1999,"claim":"Defined CDC5L as a spliceosome-associated factor conserved from yeast, addressing whether the Myb protein had an RNA-processing function.","evidence":"Immunofluorescence colocalization with splicing factors, nuclear-extract co-IP, in vitro spliceosome assembly, and yeast CEF1 depletion","pmids":["10570151"],"confidence":"High","gaps":["Whether CDC5L acts catalytically or structurally not resolved","Step of splicing affected in human system unclear"]},{"year":2000,"claim":"Demonstrated that the CDC5L complex is required specifically for the second catalytic step of splicing and joins the spliceosome in an ATP-dependent manner, distinguishing its role from assembly.","evidence":"Immunodepletion/add-back from HeLa nuclear extract with in vitro splicing and MS identification of complex members","pmids":["11101529"],"confidence":"High","gaps":["Individual subunit contributions not yet dissected","Mechanism of catalytic-step facilitation unknown"]},{"year":2000,"claim":"Linked CDC5L splicing activity to cell-cycle kinase signaling by showing cyclin E-Cdk2 phosphorylation creates a docking site for the NIPP1/PP1 FHA module.","evidence":"Yeast two-hybrid, reciprocal co-IP, nuclear-extract co-purification, and FHA-domain mutant splicing assays","pmids":["10827081"],"confidence":"High","gaps":["Precise phosphosites not mapped here","How PP1 activity modulates splicing kinetics unresolved"]},{"year":2001,"claim":"Identified the CDC5L-PLRG1 interaction (C-terminus to WD40 domain) as a direct, mechanistically essential contact for splicing.","evidence":"Co-IP, direct in vitro binding, and competitive peptide disruption in in vitro splicing","pmids":["11544257"],"confidence":"High","gaps":["Structural basis of the interface not resolved","Function of PLRG1 within the catalytic step unclear"]},{"year":2003,"claim":"Mapped additional spliceosomal interactions (hLodestar/HuF2) and confirmed CDC5L-PLRG1 essentiality, extending the interaction network required for splicing.","evidence":"Yeast two-hybrid, co-IP, and competitive peptide/inhibition in vitro splicing assays","pmids":["12927788","14576297"],"confidence":"Medium","gaps":["Role of hLodestar in assembly versus catalysis not separated","In vivo relevance of these contacts limited"]},{"year":2008,"claim":"Pinpointed CDK2 phosphorylation of CDC5L at T411/T438 as required for splicing, mechanistically connecting cell-cycle kinases to spliceosome function.","evidence":"Phosphopeptide mapping, MS, in vitro kinase assay with CDK2 inhibitor, and splicing assays with phosphosite mutants","pmids":["18583928"],"confidence":"High","gaps":["How phosphorylation alters complex behavior structurally unknown","Homodimerization function not defined"]},{"year":2009,"claim":"Revealed a splicing-independent role: CDC5L binds ATR and is required for S-phase checkpoint activation, broadening its function into the DNA-replication stress response.","evidence":"Co-IP, RNAi knockdown, Chk1/Rad17/FancD2 phosphorylation assays, and ATR-binding-deficient deletion-mutant rescue","pmids":["19633697"],"confidence":"High","gaps":["Direct biochemical role of CDC5L in ATR activation unresolved","Whether checkpoint role depends on the splicing complex unclear"]},{"year":2010,"claim":"Resolved the architecture of the human Prp19/CDC5L complex, defining a stable CDC5L/hPrp19/PRL1/SPF27 core, and characterized regulatory interactions including hnRNP-M and Akt-dependent PRP19α/14-3-3β assembly.","evidence":"Native complex purification, stoichiometry, limited proteolysis and EM; co-IP and domain-mapping for hnRNP-M and PRP19α phospho-dependent assembly","pmids":["20176811","20467437","20629186"],"confidence":"High","gaps":["Atomic structure of the complex not determined","How accessory factors remodel the core during the cycle unknown"]},{"year":2011,"claim":"Showed CTNNBL1 binds the CDC5L NLS via its armadillo domain to integrate CDC5L into the Prp19 complex, identifying a recruitment/chaperone mechanism.","evidence":"Co-IP, domain mapping, and NLS-binding assays","pmids":["21385873"],"confidence":"Medium","gaps":["Whether CTNNBL1 affects nuclear import versus complex assembly not separated"]},{"year":2014,"claim":"Connected CDC5L splicing function to mitotic fidelity, showing depletion causes mitotic catastrophe through impaired splicing of mitosis and DNA-damage genes.","evidence":"RNAi, live-cell imaging, chromosome spreads, genome-wide expression and splicing-efficiency profiling","pmids":["24675469"],"confidence":"Medium","gaps":["Which specific splicing targets drive each phenotype not fully resolved","Direct versus indirect transcript effects not separated"]},{"year":2015,"claim":"Defined CTNNBL1 as a chaperone required for Prp19 complex integrity, showing it promotes CWC15-CDC5L association via an overlapping binding region.","evidence":"Crosslinking + HDX-MS, in vitro binding, and CTNNBL1-deficient cell analysis","pmids":["26130721"],"confidence":"Medium","gaps":["Dynamics of CWC15/CTNNBL1 exchange on CDC5L not directly observed"]},{"year":2021,"claim":"Demonstrated tissue-specific, target-directed splicing by CDC5L, which directly binds and regulates SOX9, COL2A1, and WEE1 transcripts to drive chondrogenesis.","evidence":"siRNA, RNA-binding protein immunoprecipitation, splicing-efficiency assays, and cartilage rudiment culture","pmids":["34298017"],"confidence":"Medium","gaps":["Sequence determinants of CDC5L transcript selectivity unknown","Whether direct RNA contact is via Myb-like domain not established here"]},{"year":2017,"claim":"Reported direct CDC5L promoter binding and transcriptional activation activity at hTERT and other genes, supporting a DNA-binding/transcription function distinct from splicing.","evidence":"DNA pulldown, ChIP, luciferase reporter, and siRNA assays in tumor cells","pmids":["11082045","28472785","32167655"],"confidence":"Low","gaps":["Transcriptional role demonstrated in limited cell contexts without endogenous-promoter mechanism","Relationship between DNA-binding and spliceosomal pools unclear"]},{"year":2024,"claim":"Defined upstream regulation of CDC5L abundance by Prp19 (post-transcriptional/lysosomal) and by the m6A reader IGF2BP1, linking CDC5L levels to proliferation in disease contexts.","evidence":"siRNA/overexpression rescue, lysosomal inhibitors, m6A-seq, and RIP in HCC and myeloma cells","pmids":["28387715","39534570"],"confidence":"Low","gaps":["Mechanisms inferred without direct biochemical reconstitution","Generality beyond specific cancer models untested"]},{"year":null,"claim":"How CDC5L's distinct activities — spliceosomal catalysis, ATR checkpoint signaling, and Myb-mediated DNA binding/transcription — are coordinated and whether they reflect physically separate protein pools remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the human complex bound to spliceosome substrate","Mechanism integrating phosphorylation, complex assembly, and non-splicing roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,4]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[16,20]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[21,18]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4,18]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[19,7]}],"complexes":["Prp19/CDC5L complex"],"partners":["PLRG1","PRPF19","BCAS2","CTNNBL1","CWC15","ATR","NIPP1","HNRNPM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99459","full_name":"Cell division cycle 5-like protein","aliases":["Pombe cdc5-related protein"],"length_aa":802,"mass_kda":92.3,"function":"DNA-binding protein involved in cell cycle control. May act as a transcription activator. Plays a role in pre-mRNA splicing as core component of precatalytic, catalytic and postcatalytic spliceosomal complexes (PubMed:11991638, PubMed:20176811, PubMed:28076346, PubMed:28502770, PubMed:29301961, PubMed:29360106, PubMed:29361316, PubMed:30705154, PubMed:30728453). Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. The PRP19-CDC5L complex may also play a role in the response to DNA damage (DDR) (PubMed:20176811). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable)","subcellular_location":"Nucleus; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q99459/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDC5L","classification":"Common 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regulator Le.CDC5 of the mushroom Lentinula edodes: analyses of its amount in each of the stages of fruiting-body formation and its distribution in parts of the fruiting bodies.","date":"2006","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/16842359","citation_count":7,"is_preprint":false},{"pmid":"39534570","id":"PMC_39534570","title":"IGF2BP1 promotes multiple myeloma with chromosome 1q gain via increasing CDC5L expression in an m6A-dependent manner.","date":"2024","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39534570","citation_count":6,"is_preprint":false},{"pmid":"39113868","id":"PMC_39113868","title":"m6A modification of CDC5L promotes lung adenocarcinoma progression through transcriptionally regulating WNT7B expression.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39113868","citation_count":6,"is_preprint":false},{"pmid":"35313568","id":"PMC_35313568","title":"HuR Promotes the Progression of Gastric Cancer through Mediating CDC5L Expression.","date":"2022","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/35313568","citation_count":6,"is_preprint":false},{"pmid":"11694351","id":"PMC_11694351","title":"Prolactin, interleukin-2 and FGF-2 stimulate expression, nuclear distribution and DNA-binding of rat homolog of pombe Cdc5 in Nb2 T lymphoma cells.","date":"2001","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11694351","citation_count":6,"is_preprint":false},{"pmid":"20962588","id":"PMC_20962588","title":"Cdc5 blocks in vivo Rad53 activity, but not in situ activity (ISA).","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/20962588","citation_count":6,"is_preprint":false},{"pmid":"32543224","id":"PMC_32543224","title":"Identification of CDC5L as bridge gene between chronic obstructive pulmonary disease and lung 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Immunodepletion of the CDC5L complex inhibits pre-mRNA splicing product formation in vitro but does not prevent spliceosome assembly; the purified complex restores splicing activity when added back to immunodepleted extracts.\",\n      \"method\": \"Immunodepletion from HeLa nuclear extract, in vitro splicing assay, mass spectrometry identification of complex components\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with immunodepletion/add-back, multiple orthogonal methods (in vitro splicing, MS), single lab with rigorous controls\",\n      \"pmids\": [\"11101529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDC5L directly interacts with PLRG1 via the carboxyl-terminal region of CDC5L and the WD40 domain of PLRG1; disruption of this interaction by a bacterially expressed competing peptide inhibits pre-mRNA splicing in HeLa nuclear extract, demonstrating that this protein-protein interaction is essential for pre-mRNA splicing.\",\n      \"method\": \"Co-immunoprecipitation in vivo, direct in vitro binding assay, competitive peptide disruption with in vitro splicing assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution of interaction, functional disruption with competing peptide in splicing assay, multiple orthogonal methods\",\n      \"pmids\": [\"11544257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The human Prp19/CDC5L complex contains four copies of hPrp19, with a stable core comprised of CDC5L, hPrp19, PRL1, and SPF27. SPF27 directly interacts with each core component; limited proteolysis revealed a protease-resistant sub-complex of SPF27, the C-terminus of CDC5L, and N-termini of PRL1 and hPrp19. Under EM the complex has an elongated asymmetric shape (~20 nm).\",\n      \"method\": \"Native complex purification from HeLa cells, stoichiometric analysis, salt-treatment dissection, protein-protein interaction studies, limited proteolysis, electron microscopy\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural/biochemical characterization with multiple orthogonal methods (EM, proteolysis, stoichiometry, interaction mapping) in a single rigorous study\",\n      \"pmids\": [\"20176811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NIPP1, a regulatory subunit of protein phosphatase-1, interacts with CDC5L through its FHA (forkhead-associated) domain in a phosphorylation-dependent manner; CDC5L is phosphorylated by cyclin E-Cdk2, which is required for the NIPP1 FHA domain to bind CDC5L. CDC5L, NIPP1, and PP1 form a complex in rat liver nuclear extracts. Expression of the NIPP1 FHA domain in cells blocks beta-globin pre-mRNA splicing, and a mutation that abolishes FHA-CDC5L interaction also abolishes this anti-splicing effect.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-purification from nuclear extracts, in vitro splicing assay, FHA domain mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, functional splicing assay with mutagenesis, phosphorylation dependency demonstrated, multiple orthogonal methods\",\n      \"pmids\": [\"10827081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CDC5 (mammalian) colocalizes with pre-mRNA splicing factors in mammalian nuclei, associates with core spliceosomal components in nuclear extracts, and interacts with the spliceosome throughout the splicing reaction in vitro. Genetic depletion of the yeast homolog CEF1 blocks the first step of pre-mRNA processing in vivo.\",\n      \"method\": \"Immunofluorescence colocalization, nuclear extract co-immunoprecipitation, in vitro spliceosome assembly, yeast genetic depletion\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (colocalization, co-IP, in vitro splicing, genetics), independently corroborated across organisms\",\n      \"pmids\": [\"10570151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CDC5L physically interacts with the checkpoint kinase ATR; depletion of CDC5L by RNAi causes a defective S-phase cell-cycle checkpoint and cellular sensitivity to replication-fork blocking agents. CDC5L is required for activation of downstream ATR effectors Chk1, Rad17, and FancD2. A CDC5L deletion mutant unable to bind ATR fails to rescue the checkpoint deficiency in CDC5L-depleted cells.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, checkpoint assays (Chk1/Rad17/FancD2 phosphorylation), domain-mapping with deletion mutant rescue\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, domain-mapping rescue experiment, multiple downstream effector readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19633697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cell cycle-dependent phosphorylation of human CDC5L at threonines 411 and 438 (within CDK recognition sequences) is required for CDC5L-mediated pre-mRNA splicing in vitro. CDK2 phosphorylates CDC5L in vitro and in vivo; a specific CDK2 inhibitor (CVT-313) inhibits CDC5L phosphorylation. CDC5L forms homodimers in vitro and in vivo, but homodimerization and nuclear localization do not depend on phosphorylation at these sites.\",\n      \"method\": \"2D phosphopeptide mapping, nanoelectrospray mass spectrometry, in vitro splicing assay with phosphorylation-site mutants, in vitro kinase assay, in vivo radiolabeling\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, in vitro splicing functional assay, MS site identification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18583928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human CDC5 (hCdc5/CDC5L) promotes G2/M progression in mammalian cells: overexpression shortened G2 and reduced cell size, while a dominant-negative mutant lacking the C-terminal activation domain slowed G2 progression and delayed mitotic entry.\",\n      \"method\": \"Overexpression and dominant-negative mutant analysis in mammalian cells, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression/dominant-negative with cell cycle readout, no pathway mechanistic placement; replicated concept in multiple studies\",\n      \"pmids\": [\"9468527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human CDC5 binds specifically and with high affinity to a 12 bp DNA sequence through its amino terminus, and this DNA-protein interaction is capable of activating transcription. Multiple human genomic sequences with similar motifs also interact with CDC5.\",\n      \"method\": \"DNA binding assay, transcriptional activation assay, yeast selection system for genomic binding sites\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro DNA binding and transcription activation, single lab, single study\",\n      \"pmids\": [\"11082045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"hnRNP-M directly interacts with CDC5L and PLRG1 in vivo; this interaction is inhibited during heat-shock stress. A central region of hnRNP-M is required for CDC5L/PLRG1 interaction, and an hnRNP-M mutant lacking this domain is unable to modulate alternative splicing of an adeno-E1A mini-gene substrate.\",\n      \"method\": \"In vivo interaction assays, domain-mapping with truncation mutants, in vitro/in vivo alternative splicing assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction demonstrated in vivo, domain mapping, functional splicing assay with mutant, single lab\",\n      \"pmids\": [\"20467437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CTNNBL1 binds the nuclear localization sequence (NLS) of CDC5L via its armadillo domain, mediating CTNNBL1 association with the Prp19 spliceosomal complex. CTNNBL1 also interacts with Prp31 through its NLS, but via a binding specificity distinct from karyopherin α.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping, NLS-binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and binding assays with domain mapping, single lab, multiple interaction partners characterized\",\n      \"pmids\": [\"21385873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTNNBL1 enhances the association of CWC15 with CDC5L in vitro; in vivo, CTNNBL1 deficiency reduces normal levels of the Prp19 complex and impairs CWC15-CDC5L interaction. The region of CDC5L that binds CTNNBL1 overlaps with that which binds CWC15, suggesting the two proteins may exchange at the complex. CTNNBL1 thus has a chaperone function required for Prp19 complex integrity.\",\n      \"method\": \"Amine crosslinking + hydrogen-deuterium exchange MS, in vitro binding assays, in vivo complex abundance analysis, CTNNBL1-deficient cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural MS approaches plus in vitro and in vivo functional assays, single lab\",\n      \"pmids\": [\"26130721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Peptides derived from the CDC5L-PLRG1 binding interface inhibit pre-mRNA splicing in vitro; this inhibition is prevented by pre-incubating peptides with the corresponding partner protein, confirming that the direct CDC5L-PLRG1 interaction is mechanistically essential for splicing.\",\n      \"method\": \"Competitive peptide inhibition in in vitro splicing assay, rescue by recombinant partner protein\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution/competition assay with functional readout, single lab, single method\",\n      \"pmids\": [\"14576297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DAP-like kinase (Dlk/ZIP kinase) interacts with rat CDC5 (homolog of human CDC5L) in vitro, but does not phosphorylate it directly; instead, an associated kinase identified as CK2 phosphorylates CDC5. Both proteins co-localize in nuclear speckles in vivo. The interaction domain of Dlk maps to its leucine zipper, and that of CDC5 maps to its C-terminal region (residues 500-802).\",\n      \"method\": \"In vitro binding assay, in vitro kinase assay, immunofluorescence colocalization, domain mapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding and kinase assays with domain mapping, colocalization, single lab\",\n      \"pmids\": [\"11884640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"hLodestar/HuF2 (SNF2 family) interacts with CDC5L in yeast two-hybrid and HeLa nuclear extracts; a truncated hLodestar/HuF2 polypeptide overlapping the CDC5L-binding region inhibits pre-mRNA splicing by disrupting spliceosome assembly.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from HeLa nuclear extract, in vitro splicing inhibition assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-IP plus functional splicing assay, single lab\",\n      \"pmids\": [\"12927788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Alleles of yeast CEF1 (the S. cerevisiae ortholog of CDC5L) suppress second-step splicing defects caused by intron mutations, U6 snRNA mutations, or deletion of the second-step factor Prp17, and can activate alternative 3' splice sites. Genetic interactions with prp8 alleles suggest CEF1/CDC5L modulates the first-to-second-step conformational transition of the spliceosome, likely through its Myb-like domain.\",\n      \"method\": \"Genetic suppressor analysis, in vitro splicing assays with mutant alleles, epistasis with prp8 and U6 alleles\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple allele combinations, in vitro splicing assays, single lab\",\n      \"pmids\": [\"22408182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The N-terminus of S. pombe Cdc5 (CDC5L ortholog) contains two canonical Myb repeats (R1, R2) and a third domain (D3) that, while not adopting a canonical Myb fold, preferentially binds double-stranded RNA in vitro. All three domains (R1, R2, D3) are required for Cdc5 function in yeast cells.\",\n      \"method\": \"Yeast genetics (truncation mutants), NMR/structural analysis of D3, RNA binding assays (EMSA), functional complementation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural characterization plus RNA binding assays plus in vivo genetic functional assays, single lab\",\n      \"pmids\": [\"25263959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Akt phosphorylates PRP19α at Thr193, which is critical for PRP19α binding to 14-3-3β; this allows nuclear translocation and formation of a PRP19α/14-3-3β/CDC5L complex required for active spliceosome assembly during NGF-induced neuronal differentiation of PC12 cells. A nonphosphorylatable PRP19α T193A mutant loses 14-3-3β binding and acts as a dominant negative in neuronal differentiation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutant analysis, knockdown/overexpression in PC12 cells, nuclear fractionation\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, mutagenesis (T193A), dominant-negative rescue, single lab with multiple approaches\",\n      \"pmids\": [\"20629186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human CDC5 (CDC5L) nuclear import is directed by the amino-terminal domain independent of consensus nuclear localization signals or phosphorylation, while the carboxyl-terminus preferentially associates with spliceosomal complexes near RNA transcription sites during interphase. CDC5L colocalizes with Sm proteins in a cell cycle- and domain-dependent manner.\",\n      \"method\": \"Domain-deletion constructs, nuclear fractionation, immunofluorescence colocalization, cell cycle analysis\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain-deletion localization experiments with multiple markers, single lab\",\n      \"pmids\": [\"14515018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Depletion of CDC5L causes dramatic mitotic arrest, chromosome misalignments, sustained spindle assembly checkpoint activation, severe impairment of kinetochore-microtubule attachment, and DNA damage, ultimately leading to mitotic catastrophe. Genome-wide expression analysis reveals that CDC5L modulates expression of mitosis and DNA damage response genes, and pre-mRNA splicing efficiency of these genes is impaired upon CDC5L knockdown.\",\n      \"method\": \"RNAi knockdown, live-cell imaging, chromosome spread analysis, genome-wide expression profiling, splicing efficiency assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with defined mitotic phenotype and splicing mechanism, multiple readouts, single lab\",\n      \"pmids\": [\"24675469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cdc5l (CDC5L) promotes early chondrogenesis and chondrocyte proliferation by modulating pre-mRNA splicing of Sox9, Col2a1, and Wee1. Knockdown of Cdc5l in murine chondrocytes decreased Sox9 and Col2a1 expression, enhanced Wee1 expression (causing G2/M arrest), and reduced pre-mRNA splicing efficiency of Sox9 and Col2a1 while paradoxically enhancing splicing of Wee1 pre-mRNA. RNA-binding protein immunoprecipitation confirmed direct binding of Cdc5l to these target transcripts.\",\n      \"method\": \"siRNA knockdown, FACS cell cycle analysis, cartilage rudiment culture, RNA-binding protein immunoprecipitation (RIP), splicing efficiency assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi + RIP confirming direct RNA binding + splicing assays + cell cycle phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34298017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The human CDC5L gene maps to chromosome 6p21, consists of at least 16 exons spanning ~50 kb, and encodes a ~100 kDa nuclear protein. Immunocytochemistry confirmed nuclear localization. The protein contains a Myb-related DNA binding domain and nuclear localization signals in its N-terminus and a proline-rich putative transcriptional activating domain in its central region.\",\n      \"method\": \"Genomic organization mapping, immunocytochemistry, Western blot, Northern blot\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by immunocytochemistry, genomic characterization only; no direct functional experiment beyond confirming nuclear localization\",\n      \"pmids\": [\"9598309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human CDC5L (PCDC5RP) translocates rapidly from cytoplasm to nucleus upon serum stimulation of cultured cells, correlating temporally with increased CDC5L phosphorylation, suggesting it transduces cytoplasmic signals to the nucleus.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, phosphorylation analysis after serum stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization observation with phosphorylation correlation, no mechanistic follow-up, single study\",\n      \"pmids\": [\"9038199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDC5L binds directly to the hTERT promoter (identified by pulldown with biotin-labeled hTERT promoter and confirmed by ChIP assay) and acts as a transcriptional activator of hTERT, as shown by luciferase reporter assay. CDC5L knockdown inhibits tumor growth by down-regulating hTERT expression.\",\n      \"method\": \"Biotin-labeled DNA pulldown, ChIP assay, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ChIP and reporter assay with limited mechanistic depth\",\n      \"pmids\": [\"28472785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDC5L protein binds directly to the PEAK1 gene promoter to promote its transcription, as confirmed by chromatin immunoprecipitation (ChIP) assay in ovarian cancer cells.\",\n      \"method\": \"ChIP assay, transcriptional reporter, siRNA knockdown\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP assay for direct promoter binding, single lab, cancer-cell context only\",\n      \"pmids\": [\"32167655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Prp19 regulates CDC5L protein levels post-transcriptionally: silencing Prp19 in HCC cells inhibits Cdc5L mRNA translation and facilitates lysosome-mediated degradation of CDC5L protein. Overexpression of CDC5L partially rescues the cell cycle arrest caused by Prp19 knockdown, placing Prp19 upstream of CDC5L in the mitotic progression pathway.\",\n      \"method\": \"siRNA knockdown, overexpression rescue, lysosomal inhibitor experiments, Western blot, flow cytometry\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanism inferred from rescue and inhibitor experiments without direct biochemical reconstitution\",\n      \"pmids\": [\"28387715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP1, an m6A reader, binds to m6A sites on CDC5L mRNA and up-regulates CDC5L protein abundance post-transcriptionally. Knockdown or mutation of CDC5L attenuates the pro-proliferative effect of IGF2BP1 in multiple myeloma cells with chromosome 1q gain.\",\n      \"method\": \"m6A sequencing, RIP assay, siRNA knockdown, mutant analysis, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanism is post-transcriptional regulation of CDC5L mRNA by m6A reader; RIP and functional rescue but limited mechanistic depth on CDC5L itself\",\n      \"pmids\": [\"39534570\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDC5L (human CDC5/hCDC5/PCDC5RP) is a core component of the Prp19/CDC5L spliceosomal complex required for the second catalytic step of pre-mRNA splicing; it directly interacts with PLRG1 (via its C-terminal domain binding the PLRG1 WD40 domain), with CTNNBL1 (via its NLS), and with the spliceosome throughout the splicing reaction, while its splicing activity is regulated by CDK2-mediated phosphorylation at T411/T438. Beyond splicing, CDC5L interacts with the checkpoint kinase ATR and is required for ATR-mediated S-phase checkpoint activation (including Chk1, Rad17, and FancD2 phosphorylation); it also functions as a site-specific DNA-binding and transcriptional activator through its N-terminal Myb repeats, can promote G2/M progression when overexpressed, and regulates the splicing of chondrogenic genes (SOX9, COL2A1, WEE1) in chondrocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDC5L is a core component of the human Prp19/CDC5L spliceosomal complex and is required for the second catalytic step of pre-mRNA splicing; it incorporates into the spliceosome in an ATP-dependent step and associates with the spliceosome throughout the reaction, with immunodepletion blocking splicing product formation without preventing spliceosome assembly [#0, #4]. Within the complex it forms a stable core with hPrp19, PRL1, and SPF27, in which SPF27 contacts each core subunit and a protease-resistant subcomplex includes the C-terminus of CDC5L [#2]. CDC5L makes a direct, splicing-essential interaction with PLRG1 through its C-terminal region binding the PLRG1 WD40 domain, and competing peptides that disrupt this interface abolish splicing in vitro [#1, #12]. Its incorporation and complex integrity are mediated by CTNNBL1, which binds the CDC5L nuclear localization sequence via its armadillo domain and functions as a chaperone that supports CWC15-CDC5L association and overall Prp19 complex levels [#10, #11]. Splicing activity is gated by cell-cycle phosphorylation: CDK2 phosphorylates CDC5L at T411/T438, an event required for splicing, while NIPP1/PP1 docks onto cyclin E-Cdk2-phosphorylated CDC5L through its FHA domain [#6, #3]. Beyond splicing, CDC5L physically associates with the checkpoint kinase ATR and is required for ATR-dependent S-phase checkpoint signaling, including phosphorylation of Chk1, Rad17, and FancD2 [#5]. Loss of CDC5L causes mitotic catastrophe with chromosome misalignment, impaired kinetochore-microtubule attachment, and defective splicing of mitosis and DNA-damage-response genes [#19], and in chondrocytes CDC5L directly binds and regulates splicing of SOX9, COL2A1, and WEE1 to drive chondrogenesis [#20]. The N-terminal Myb-like repeats confer site-specific DNA binding and transcriptional activation activity [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established CDC5L as a nuclear ~100 kDa protein with N-terminal Myb-related DNA-binding domain and a central proline-rich activation domain, and showed overexpression promotes G2/M progression — first hint of a cell-cycle role.\",\n      \"evidence\": \"Genomic organization mapping and overexpression/dominant-negative cell-cycle analysis in mammalian cells\",\n      \"pmids\": [\"9598309\", \"9468527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"G2/M effect inferred from over/under-expression without endogenous pathway placement\", \"Molecular function (splicing) not yet defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined CDC5L as a spliceosome-associated factor conserved from yeast, addressing whether the Myb protein had an RNA-processing function.\",\n      \"evidence\": \"Immunofluorescence colocalization with splicing factors, nuclear-extract co-IP, in vitro spliceosome assembly, and yeast CEF1 depletion\",\n      \"pmids\": [\"10570151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDC5L acts catalytically or structurally not resolved\", \"Step of splicing affected in human system unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that the CDC5L complex is required specifically for the second catalytic step of splicing and joins the spliceosome in an ATP-dependent manner, distinguishing its role from assembly.\",\n      \"evidence\": \"Immunodepletion/add-back from HeLa nuclear extract with in vitro splicing and MS identification of complex members\",\n      \"pmids\": [\"11101529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual subunit contributions not yet dissected\", \"Mechanism of catalytic-step facilitation unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked CDC5L splicing activity to cell-cycle kinase signaling by showing cyclin E-Cdk2 phosphorylation creates a docking site for the NIPP1/PP1 FHA module.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, nuclear-extract co-purification, and FHA-domain mutant splicing assays\",\n      \"pmids\": [\"10827081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise phosphosites not mapped here\", \"How PP1 activity modulates splicing kinetics unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the CDC5L-PLRG1 interaction (C-terminus to WD40 domain) as a direct, mechanistically essential contact for splicing.\",\n      \"evidence\": \"Co-IP, direct in vitro binding, and competitive peptide disruption in in vitro splicing\",\n      \"pmids\": [\"11544257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the interface not resolved\", \"Function of PLRG1 within the catalytic step unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped additional spliceosomal interactions (hLodestar/HuF2) and confirmed CDC5L-PLRG1 essentiality, extending the interaction network required for splicing.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and competitive peptide/inhibition in vitro splicing assays\",\n      \"pmids\": [\"12927788\", \"14576297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of hLodestar in assembly versus catalysis not separated\", \"In vivo relevance of these contacts limited\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Pinpointed CDK2 phosphorylation of CDC5L at T411/T438 as required for splicing, mechanistically connecting cell-cycle kinases to spliceosome function.\",\n      \"evidence\": \"Phosphopeptide mapping, MS, in vitro kinase assay with CDK2 inhibitor, and splicing assays with phosphosite mutants\",\n      \"pmids\": [\"18583928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation alters complex behavior structurally unknown\", \"Homodimerization function not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a splicing-independent role: CDC5L binds ATR and is required for S-phase checkpoint activation, broadening its function into the DNA-replication stress response.\",\n      \"evidence\": \"Co-IP, RNAi knockdown, Chk1/Rad17/FancD2 phosphorylation assays, and ATR-binding-deficient deletion-mutant rescue\",\n      \"pmids\": [\"19633697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical role of CDC5L in ATR activation unresolved\", \"Whether checkpoint role depends on the splicing complex unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the architecture of the human Prp19/CDC5L complex, defining a stable CDC5L/hPrp19/PRL1/SPF27 core, and characterized regulatory interactions including hnRNP-M and Akt-dependent PRP19α/14-3-3β assembly.\",\n      \"evidence\": \"Native complex purification, stoichiometry, limited proteolysis and EM; co-IP and domain-mapping for hnRNP-M and PRP19α phospho-dependent assembly\",\n      \"pmids\": [\"20176811\", \"20467437\", \"20629186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the complex not determined\", \"How accessory factors remodel the core during the cycle unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CTNNBL1 binds the CDC5L NLS via its armadillo domain to integrate CDC5L into the Prp19 complex, identifying a recruitment/chaperone mechanism.\",\n      \"evidence\": \"Co-IP, domain mapping, and NLS-binding assays\",\n      \"pmids\": [\"21385873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CTNNBL1 affects nuclear import versus complex assembly not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CDC5L splicing function to mitotic fidelity, showing depletion causes mitotic catastrophe through impaired splicing of mitosis and DNA-damage genes.\",\n      \"evidence\": \"RNAi, live-cell imaging, chromosome spreads, genome-wide expression and splicing-efficiency profiling\",\n      \"pmids\": [\"24675469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific splicing targets drive each phenotype not fully resolved\", \"Direct versus indirect transcript effects not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined CTNNBL1 as a chaperone required for Prp19 complex integrity, showing it promotes CWC15-CDC5L association via an overlapping binding region.\",\n      \"evidence\": \"Crosslinking + HDX-MS, in vitro binding, and CTNNBL1-deficient cell analysis\",\n      \"pmids\": [\"26130721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dynamics of CWC15/CTNNBL1 exchange on CDC5L not directly observed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated tissue-specific, target-directed splicing by CDC5L, which directly binds and regulates SOX9, COL2A1, and WEE1 transcripts to drive chondrogenesis.\",\n      \"evidence\": \"siRNA, RNA-binding protein immunoprecipitation, splicing-efficiency assays, and cartilage rudiment culture\",\n      \"pmids\": [\"34298017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence determinants of CDC5L transcript selectivity unknown\", \"Whether direct RNA contact is via Myb-like domain not established here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reported direct CDC5L promoter binding and transcriptional activation activity at hTERT and other genes, supporting a DNA-binding/transcription function distinct from splicing.\",\n      \"evidence\": \"DNA pulldown, ChIP, luciferase reporter, and siRNA assays in tumor cells\",\n      \"pmids\": [\"11082045\", \"28472785\", \"32167655\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Transcriptional role demonstrated in limited cell contexts without endogenous-promoter mechanism\", \"Relationship between DNA-binding and spliceosomal pools unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined upstream regulation of CDC5L abundance by Prp19 (post-transcriptional/lysosomal) and by the m6A reader IGF2BP1, linking CDC5L levels to proliferation in disease contexts.\",\n      \"evidence\": \"siRNA/overexpression rescue, lysosomal inhibitors, m6A-seq, and RIP in HCC and myeloma cells\",\n      \"pmids\": [\"28387715\", \"39534570\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanisms inferred without direct biochemical reconstitution\", \"Generality beyond specific cancer models untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDC5L's distinct activities — spliceosomal catalysis, ATR checkpoint signaling, and Myb-mediated DNA binding/transcription — are coordinated and whether they reflect physically separate protein pools remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the human complex bound to spliceosome substrate\", \"Mechanism integrating phosphorylation, complex assembly, and non-splicing roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [16, 20]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21, 18]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [19, 7]}\n    ],\n    \"complexes\": [\n      \"Prp19/CDC5L complex\"\n    ],\n    \"partners\": [\n      \"PLRG1\",\n      \"PRPF19\",\n      \"BCAS2\",\n      \"CTNNBL1\",\n      \"CWC15\",\n      \"ATR\",\n      \"NIPP1\",\n      \"HNRNPM\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}