Affinage

CDK12

Cyclin-dependent kinase 12 · UniProt Q9NYV4

Length
1490 aa
Mass
164.2 kDa
Annotated
2026-06-09
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDK12 is a transcriptional cyclin-dependent kinase that pairs with cyclin K to phosphorylate the Ser2 (and Ser5) residues of the RNA polymerase II C-terminal domain, controlling productive transcription elongation genome-wide (PMID:22012619, PMID:22988298, PMID:24662513). Its kinase activity is required for the processive elongation of long, multi-exon genes: loss of CDK12 produces gene-length-dependent elongation defects and widespread premature cleavage and intronic polyadenylation, preferentially extinguishing expression of DNA damage response genes such as BRCA1, ATR, FANCI, and FANCD2, which are unusually rich in intronic poly(A) sites (PMID:30487607, PMID:30988284, PMID:31347271). Mechanistically, CDK12 sustains elongation by maintaining the association of PAF1 complex subunits (LEO1, CDC73) and SPT6 with elongating RNAPII—phosphorylating LEO1 to promote PAF1C engagement—and by coupling transcription to co-transcriptional splicing through SF3B1 recruitment to RNAPII phosphorylated on Ser2 (PMID:32805052, PMID:37205756, PMID:37026485). The CDK12/cyclin K complex also phosphorylates substrates beyond the CTD, including the translational repressor 4E-BP1 at Ser65/Thr70 to promote cap-dependent translation of mTORC1-target mRNAs such as CHK1 (PMID:30819820). Through these activities CDK12 enforces genomic stability: it is recruited to damaged genes via PARP-dependent DDR signaling to repress their transcription and resolve transcription-replication conflicts, and its inactivation generates a 'BRCAness' phenotype and focal genomic instability (PMID:39155303, PMID:31668947, PMID:39368479). Cancer-associated CDK12 mutations disrupt CDK12/cyclin K complex formation and coordinately downregulate homologous recombination genes (PMID:25712099), and CDK12 has been exploited therapeutically through covalent inhibitors and molecular glue degraders that recruit the DDB1-CUL4-RBX1 ligase to destroy cyclin K (PMID:27571479, PMID:32804079, PMID:33753926). CDK12 is partially redundant with its paralog CDK13, and CDK12-mutant tumors are selectively dependent on CDK13 (PMID:32917631, PMID:39368479).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 Medium

    Established the first link between CDK12 and the transcription machinery by showing it localizes to nuclear speckles and can phosphorylate the RNAPII CTD.

    Evidence Anti-CrkRS immunoprecipitation with in vitro CTD kinase assay and co-localization imaging with SC35

    PMID:11683387

    Open questions at the time
    • No cognate cyclin partner identified
    • In vitro kinase activity not yet mapped to specific CTD residues
    • Cellular consequences of CDK12 loss unknown
  2. 2006 Medium

    Showed CDK12 forms a CDK/cyclin complex and can influence alternative splicing, framing it as a kinase coupling transcription to RNA processing.

    Evidence Co-IP, siRNA with E1a minigene splicing assay, and domain mapping (cyclin L1/L2)

    PMID:16537916

    Open questions at the time
    • Cyclin L partners were later superseded by cyclin K as the physiological partner
    • Direct splicing substrates not defined
    • Genome-wide splicing role not addressed
  3. 2010 High

    Defined CDK12 as a metazoan transcription-elongation CTD kinase by demonstrating cyclin K association, 3'-end gene enrichment, and Ser2 phosphorylation dependence.

    Evidence In vitro kinase assay, ChIP on Drosophila genes, RNAi with CTD phospho-readout, and yeast complementation

    PMID:20952539

    Open questions at the time
    • Specific target gene programs not yet defined
    • Link to DNA damage response not established
  4. 2011 High

    Identified cyclin K as the functional partner and connected CDK12 activity to a specific gene program—DNA damage response genes—whose loss causes genomic instability.

    Evidence Co-IP, microarray, nuclear run-on, ChIP, and siRNA with DNA-damage sensitivity assays

    PMID:22012619 PMID:22988298

    Open questions at the time
    • Mechanism by which DDR genes are selectively affected not yet known
    • Direct non-CTD substrates undefined
  5. 2014 High

    Resolved the structural basis of CDK12/cyclin K kinase activity and its substrate preference for pre-phosphorylated CTD.

    Evidence X-ray crystallography of CDK12/CycK with in vitro kinase assays and CAK co-expression

    PMID:24662513

    Open questions at the time
    • Structure of full-length protein with intrinsically disordered regions not resolved
    • Substrate docking for non-CTD targets unknown
  6. 2015 High

    Demonstrated that cancer-associated CDK12 mutations act by disrupting complex formation and coordinately suppressing homologous recombination genes, establishing CDK12 as an HR-deficiency driver.

    Evidence Biochemical reconstitution of mutant CDK12/CycK complexes, patient mRNA expression, and HR repair functional assay

    PMID:25712099

    Open questions at the time
    • Precise molecular step linking kinase loss to HR gene downregulation not yet defined
  7. 2015 High

    Confirmed CDK12 is essential in vivo and selectively governs DDR gene expression, distinguishing it from a global transcription factor.

    Evidence Conditional knockout mouse with blastocyst phenotyping, 53BP1 foci imaging, and qRT-PCR of DDR genes; Drosophila RNAi screens

    PMID:25561469 PMID:26658019 PMID:26911346

    Open questions at the time
    • Whether bulk CTD phosphorylation versus gene-selective effects dominate remained debated across cell systems
  8. 2018 High

    Identified the central mechanism—suppression of intronic polyadenylation to permit full-length transcripts—explaining why long HR genes are selectively lost upon CDK12 inactivation.

    Evidence 3' end RNA-seq in mESCs with CDK12 knockdown/inhibition, intronic poly(A) bioinformatics, and human tumor validation

    PMID:30487607

    Open questions at the time
    • Identity of the direct processing-factor substrates not yet defined here
  9. 2019 High

    Linked CDK12 to gene-length-dependent elongation processivity and directly identified pre-mRNA processing factors as phosphorylation substrates regulating premature cleavage/polyadenylation.

    Evidence RNA-seq, ChIP-seq for RNAPII/P-Ser2, analog-sensitive inhibition, and phosphoproteomics

    PMID:30988284 PMID:31347271

    Open questions at the time
    • Bulk versus gene-body redistribution of P-Ser2 reconciled but absolute mechanism of processivity loss incomplete
  10. 2019 High

    Extended CDK12 substrate repertoire beyond transcription by showing direct phosphorylation of 4E-BP1 to control cap-dependent translation, coupling CDK12 to mTORC1 signaling and mitotic fidelity.

    Evidence In vitro kinase assay with phosphosite mutagenesis, RIP-seq, Ribo-seq, and chromosome-dynamics imaging

    PMID:30819820

    Open questions at the time
    • Relative contribution of translational versus transcriptional CDK12 functions to phenotypes not quantified
  11. 2020 High

    Defined the molecular cause of the elongation defect as loss of PAF1C subunits (LEO1, CDC73) and SPT6 from elongating RNAPII, with global Ser2/Ser5 reduction.

    Evidence TT-seq, mNET-seq, rapid CDK12 inhibition, ChIP, and western blot

    PMID:32805052

    Open questions at the time
    • Direct phosphorylation event causing elongation factor loss not yet pinpointed (resolved later for LEO1)
  12. 2020 High

    Established functional redundancy between CDK12 and CDK13, showing dual but not single inhibition collapses RNAPII processivity and viability.

    Evidence Analog-sensitive CDK12/CDK13 chemical-genetics with RNA-seq, mNET-seq, elongation-rate measurement, and viability assays

    PMID:32917631

    Open questions at the time
    • Division of labor between the two paralogs at specific gene classes incompletely mapped
  13. 2020 High

    Revealed that CDK12/cyclin K is druggable via molecular glues that hijack the DDB1-CUL4-RBX1 ligase to degrade cyclin K, providing a therapeutic mechanism distinct from kinase inhibition.

    Evidence Genetic screening, biochemical reconstitution, ubiquitination assays, and substrate-phospho readouts (HQ461, NCT02)

    PMID:32804079 PMID:34289372

    Open questions at the time
    • Why TP53 deficiency sensitizes to CCNK degradation not fully resolved
  14. 2023 High

    Provided the direct substrate-level mechanism for elongation control by showing CDK12 phosphorylates LEO1 to promote PAF1C engagement, opposed by the INTAC phosphatase, and couples to splicing via SF3B1.

    Evidence Phosphoproteomics, in vitro kinase assay, phospho-mutagenesis, ChIP-seq, and Co-IP (LEO1, INTAC, SF3B1)

    PMID:37026485 PMID:37205756

    Open questions at the time
    • Stoichiometry and dynamics of the kinase-phosphatase balance not quantified
  15. 2024 High

    Identified a chromatin-recruitment function whereby CDK12 is brought to damaged genes by PARP-dependent DDR signaling to repress transcription and resolve transcription-replication conflicts, mechanistically linking CDK12 loss to genomic instability.

    Evidence CDK12 ChIP at damaged genes, KO/inhibition DDR assays, MYC-overexpression combinations, DNA fiber TRC assays, and γH2AX foci; conditional prostate KO and organoid models

    PMID:39155303 PMID:39368479

    Open questions at the time
    • Precise reader of PARP signaling that recruits CDK12 not identified
    • Connection between transcriptional repression and TRC resolution mechanistically incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDK12's distinct activities—CTD/elongation control, LEO1/PAF1C regulation, 4E-BP1 phosphorylation, and DDR-gene recruitment—are coordinated and differentially deployed across cell types and gene classes remains unresolved.
  • No unified model integrating transcriptional, translational, and DNA-damage-response functions
  • Mechanism of gene-selectivity (long vs short, DDR vs lineage genes) not fully explained
  • Functional partition between CDK12 and CDK13 incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0140110 transcription regulator activity 4 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-73894 DNA Repair 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1640170 Cell Cycle 3
Partners
4E-BP1CCNKCDC73CDK13DDB1LEO1SF3B1THOC5
Complex memberships
CDK12-cyclin K complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 CDK12 (CrkRS) colocalizes with SC35 speckles and spliceosome components in nuclear speckles, and anti-CrkRS immunoprecipitates phosphorylate the CTD of RNA polymerase II in vitro, suggesting a role as a novel link between transcription and splicing machinery. Anti-CrkRS immunoprecipitation with in vitro CTD kinase assay; fluorescence microscopy/immunostaining co-localization with SC35 and hyperphosphorylated RNAPII Journal of cell science Medium 11683387
2006 CDK12 interacts with cyclin L1 and cyclin L2 through its kinase domain, forms a bona fide CDK/cyclin complex, and regulates alternative splicing of an E1a minigene; the splicing activity is potentiated by cyclin L1's cyclin domain and is antagonized by SF2/ASF and SC35. Co-immunoprecipitation, siRNA knockdown with minigene splicing assay, domain mapping Molecular and cellular biology Medium 16537916
2010 Drosophila CDK12 (dCDK12) is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1; it associates with cyclin K, is enriched at 3' ends of active genes relative to RNAPII, phosphorylates the CTD in vitro, and RNAi knockdown reduces Ser2 phosphorylation of the CTD; siRNA knockdown of human CDK12 in HeLa cells also alters CTD phosphorylation state. In vitro CTD kinase assay with purified dCDK12; ChIP on polytene chromosomes and active genes; RNAi knockdown with CTD phosphorylation readout (western blot); yeast complementation with chimeric kinases Genes & development High 20952539
2011 A 70-kDa cyclin K (CycK) binds CDK12 to form the CycK/CDK12 complex, which phosphorylates Ser2 of the RNAPII CTD and transcriptionally regulates a subset of genes including DNA damage response genes (BRCA1, ATR, FANCI, FANCD2); depletion of CycK/CDK12 causes spontaneous DNA damage and sensitivity to DNA damaging agents. Co-immunoprecipitation; expression microarrays; nuclear run-on assays; ChIP with RNAPII antibodies; siRNA depletion with DNA damage sensitivity assays Genes & development High 22012619
2012 Cyclin K1 (65-kDa isoform) is the primary endogenous cyclin partner for CDK12/CrkRS; CDK12 is dependent on cyclin K1 for its kinase activity toward the CTD of RNAPII, and siRNA knockdown of CDK12 or cyclin K1 has similar effects on luciferase reporter gene expression. Immunoprecipitation and mass spectrometry; siRNA knockdown; kinase activity assay; luciferase reporter assay Molecular and cellular biology High 22988298
2014 Crystal structure of CDK12/CycK reveals an open conformation similar to CDK9/CycT; CDK12 contains a C-terminal extension that contacts the ATP ribose via an HE motif and polybasic cluster conserved in transcriptional CDKs; CDK12/CycK shows highest activity on CTD substrate prephosphorylated at Ser7; T-loop phosphorylation requires coexpression with a CDK-activating kinase. X-ray crystallography; in vitro kinase assays with CTD peptide substrates; co-expression with CDK-activating kinase Nature communications High 24662513
2014 CDK12 and CDK13 regulate axonal elongation through a common signaling pathway that modulates CDK5 expression; depletion of CDK12 in P19 neuronal cells and cortical neurons reduces CDK5 mRNA and protein levels and shortens axonal length; overexpression of CDK5 partially rescues the neurite outgrowth defect. siRNA knockdown in P19 cells; microarray gene expression; Western blot; conditional knockout mouse; rescue by CDK5 overexpression Experimental neurology Medium 24999027
2015 Most CDK12 mutations found in high-grade serous ovarian carcinoma prevent formation of the CDK12/CycK complex, rendering the kinase inactive; these mutations cause coordinated downregulation of homologous recombination genes; mutant CDK12 proteins fail to stimulate HR-mediated DNA double-strand break repair. Biochemical reconstitution of CDK12/CycK complexes with cancer-associated mutants; mRNA expression analysis of patient samples; structural modeling; HR repair functional assay Nucleic acids research High 25712099
2015 CDK12 depletion in mice causes embryonic lethality shortly after implantation; CDK12-null blastocysts exhibit increased apoptosis, spontaneous DNA damage (53BP1 foci), and reduced expression of DNA damage response genes (Atr, Brca1, Fanci, Fancd2). Conditional CDK12 knockout mouse; blastocyst outgrowth culture; immunofluorescence (53BP1 foci); qRT-PCR of DDR genes Cell death and differentiation High 26658019
2015 CDK12 and CDK13 associate with numerous RNA processing factors in vivo; CDK12 and CDK13 depletion preferentially affects expression of DNA damage response and snoRNA genes respectively, and leads to defects in RNA processing; CDK12/CDK13 knockdown did not affect bulk CTD phosphorylation levels in HCT116 cells. Flag-tag immunoprecipitation and mass spectrometry; siRNA knockdown with RNA-seq; in vitro and in vivo CTD phosphorylation assays Molecular and cellular biology Medium 25561469
2015 Analog-sensitive CDK12 cell line generated by CRISPR/Cas9 shows that inhibition of CDK12 perturbs CTD phosphorylation patterns and arrests cellular proliferation, directly linking CDK12 kinase activity to these phenotypes. CRISPR/Cas9 knock-in of analog-sensitive CDK12 allele; chemical-genetic inhibition; western blot for CTD phosphorylation; cell proliferation assay Biochimica et biophysica acta Medium 26189575
2015 Drosophila CDK12 is a gene-selective RNA Pol II kinase required for Nrf2 target gene expression and stress-activated gene expression; CDK12 is not essential for bulk mRNA transcription. RNAi screen in Drosophila S2 cells; transcriptome analysis; in vivo genetic analysis Scientific reports Medium 26911346
2015 CDK12 antagonizes heterochromatin enrichment in Drosophila; loss of CDK12 induces ectopic accumulation of HP1 on euchromatic arms (prominently on X chromosome), within long neuronal genes, reducing their transcription and causing defects in courtship learning. ChIP-seq for HP1; fluorescence microscopy; neuronal gene expression analysis; behavioral learning assay in Drosophila CDK12 mutants PNAS Medium 26508632
2016 CDK12 covalent inhibitor THZ531, which targets a cysteine outside the kinase domain (as determined by co-crystallization with CDK12-cyclin K), causes loss of elongating and hyperphosphorylated RNAPII, decreases expression of DNA damage response genes and super-enhancer-associated transcription factor genes, and induces apoptosis. Co-crystallization of THZ531 with CDK12-cyclin K; RNA-seq; western blot for elongating RNAPII; apoptosis assays Nature chemical biology High 27571479
2017 CDK12 primarily regulates alternative last exon (ALE) splicing in a gene- and cell type-specific manner; in breast cancer cells, CDK12 regulates ALE splicing of ATM and DNAJB6, and CDK12 levels directly correlate with DNAJB6 isoform levels and cell invasiveness in xenografts. Global mRNA transcript analysis (RNA-seq); CDK12 knockdown/overexpression; xenograft invasion assays Nucleic acids research Medium 28334900
2017 Cdk12 is required for migration of late-arising cortical neurons; conditional Cdk12 deletion in neural progenitor cells causes G2/M accumulation, reduced DDR gene expression, increased DNA double-strand breaks, and misalignment of cortical layers; CDK5 overexpression partially rescues neuronal migration defects. Conditional knockout mouse; immunofluorescence; BrdU labeling; in utero electroporation; CDK5 rescue experiment Cerebral cortex Medium 27073218
2018 CDK12 globally suppresses intronic polyadenylation events, enabling production of full-length gene products; HR genes harbor more intronic polyadenylation sites than other expressed genes, making them particularly sensitive to CDK12 loss; this mechanism is conserved in human tumors with CDK12 loss-of-function mutations. 3' end RNA-seq in mouse embryonic stem cells; CDK12 knockdown/inhibition; bioinformatic analysis of intronic poly(A) sites; analysis of human tumor samples with CDK12 mutations Nature High 30487607
2018 CDK12 is required for transcriptional regulation of noncanonical NF-κB components; CDK12 inhibition prevents LTβR- and FN14-dependent expression of MAP3K14 (NIK) and NIK accumulation by reducing phosphorylation of the RNAPII CTD, thereby blocking nuclear translocation of p52. High-content phenotypic screening; chemoproteomics (CDK12 target ID); siRNA knockdown; CDK inhibitor treatment; western blot for NF-κB pathway components and RNAPII-CTD phosphorylation Science signaling Medium 30065029
2019 CDK12 phosphorylates the mRNA 5' cap-binding repressor 4E-BP1 at Ser65 and Thr70; mTORC1 primes 4E-BP1 at T37/T46 to facilitate subsequent CDK12 phosphorylation; this controls the exchange of 4E-BP1 with eIF4G at the 5' cap of CHK1 and other mRNAs, promoting translation of mTORC1-dependent mRNAs; CDK12 loss causes mitotic chromosome misalignment and segregation defects. In vitro kinase assay; phosphosite mutagenesis; RIP-seq; Ribo-seq; confocal imaging of chromosome dynamics; CDK12/CCNK depletion Genes & development High 30819820
2019 CDK12 inhibition in cancer cells causes gene length-dependent elongation defects, inducing premature cleavage and polyadenylation (PCPA) and loss of expression of long (>45 kb) genes enriched for DDR genes; phosphoproteomic analysis shows CDK12 directly phosphorylates pre-mRNA processing factors regulating PCPA. RNA-seq; CDK12 inhibition (THZ531); phosphoproteomics; bioinformatic analysis of intronic poly(A) sites and gene length Nature communications High 30988284
2019 CDK12 kinase activity is required for transcription of core DNA replication genes and G1/S progression; CDK12 inhibition triggers RNAPII processivity defects (loss of reads at 3' ends of long, poly(A)-signal-rich genes) without globally reducing RNAPII-Ser2 phosphorylation, but individual CDK12-dependent genes show a shift of P-Ser2 peaks into the gene body. Chemical-genetic analog-sensitive CDK12 inhibition; RNA-seq; ChIP-seq for RNAPII and P-Ser2 EMBO reports High 31347271
2019 CDK12 inhibition (THZ531) preferentially suppresses expression of DNA repair-related genes and induces strong DNA damage response in HCC cells; the combination with sorafenib shows striking synergy by inducing apoptosis or senescence, with THZ531 impairing adaptive responses to sorafenib. shRNA knockdown; THZ531 treatment; RNA-seq; apoptosis/senescence assays; in vivo xenograft combination treatment Gut Medium 31519701
2019 CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate the MAPK signaling pathway in gastric cancer cells. Mass spectrometry; co-immunoprecipitation; kinase assay; computer docking; RNAi knockdown; xenograft models Theranostics Medium 32483448
2020 CDK12 inhibition or loss results in premature cleavage and poly(adenylation) of DDR genes, suppresses expression of core DNA damage response proteins, and provokes a 'BRCAness' phenotype with deficiencies in DNA damage repair. SR-4835 (selective CDK12/CDK13 inhibitor); RNA-seq; DNA damage repair assays in TNBC cells Cancer cell Medium 31668947
2020 Molecular glue HQ461 promotes an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of cyclin K (CCNK); CCNK degradation compromises CDK12 function, reduces phosphorylation of a CDK12 substrate, and downregulates DDR genes. Loss-of-function and gain-of-function genetic screening; biochemical reconstitution; ubiquitination assay; western blot for CDK12 substrate phosphorylation; structure-activity relationship analysis eLife High 32804079
2020 CDK12 inhibition causes a genome-wide defect in transcription elongation and global reduction of CTD Ser2 and Ser5 phosphorylation; the elongation defect is explained by the loss of elongation factors LEO1 and CDC73 (PAF1 complex subunits) and SPT6 from newly-elongating RNAPII. TT-seq (transient transcriptome sequencing); mNET-seq for CTD phosphorylation; rapid CDK12 inhibition; western blot; ChIP Nucleic acids research High 32805052
2020 Dual inhibition of CDK12 and CDK13 with analog-sensitive kinase variants causes widespread use of alternative 3' polyadenylation sites and extensive transcriptional changes; single inhibition of CDK12 or CDK13 has minimal effect on cell viability, but dual inhibition potently induces cell death and reduces RNAPII CTD phosphorylation and elongation rates and processivity, demonstrating substantial redundancy between CDK12 and CDK13. CRISPR-Cas9 homology-directed repair to generate analog-sensitive CDK12 and CDK13; chemical-genetic dual inhibition; RNA-seq; mNET-seq; RNAPII elongation rate measurement; cell viability assay Science advances High 32917631
2020 CDK12 selectively suppresses CDK12-inhibition-sensitive transcripts (CDK12-ISTs) including prostate lineage-specific genes, with super-enhancer-associated genes being particularly sensitive; CDK12 inhibition downregulates AR signaling and synergizes with AR antagonists through attenuation of H3K27ac on AR targets. CRISPR screen; THZ531 CDK12 inhibitor; RNA-seq; ChIP-seq for H3K27ac and super-enhancers; cell viability assays Cell death & disease Medium 34315855
2020 CDK12 inhibition activates the MAPK pathway in breast cancer cells (ERα-positive), causing loss of ER dependence and resistance to endocrine therapies including tamoxifen, ICI 182780, and estrogen deprivation. RNA interference screen; MAPK pathway activation western blot; cell viability assays with endocrine therapies; siRNA knockdown of CRK7/CDK12 Carcinogenesis Medium 19651820
2021 BSJ-4-116, a selective CDK12 degrader (PROTAC), selectively degrades CDK12 over CDK13 as assessed by quantitative proteomics; selective CDK12 degradation results in premature cleavage and poly(adenylation) of DDR genes; two point mutations in CDK12 confer resistance to BSJ-4-116. PROTAC degrader design; quantitative proteomics; RNA-seq for poly(A) site usage; CRISPR-mediated resistance mutation identification; cell viability assays Nature chemical biology High 33753926
2021 NCT02 acts as a molecular glue that induces ubiquitination and proteasomal degradation of cyclin K (CCNK) and its complex partner CDK12 in colorectal cancer; CCNK/CDK12 degradation sensitivity is associated with TP53 deficiency. Small molecule screen; ubiquitination assay; western blot for CCNK and CDK12; CCNK/CDK12 knockout; in vitro and in vivo tumor growth assays; patient-derived xenografts Cell reports Medium 34289372
2022 CDK12 regulates co-transcriptional splicing and RNA turnover; acute CDK12 inhibition causes intragenic premature termination in >600 genes, reduces transcriptional readthrough, suppresses co-transcriptional splicing, and increases degradation of transcripts from DNA damage response genes. Nascent RNA Bru-seq and BruChase-seq; CDK12 inhibition; bioinformatic analysis of premature termination and splicing iScience Medium 36111258
2022 The RAS/MAPK pathway regulates CDK12 activity; melanoma cells with RAS/MAPK pathway activation harbor constitutively high CDK12 activity; CDK12 inhibition decreases expression of long multi-exon genes including DNA repair genes and promotes expression of short genes including AP-1 and NF-κB targets. CDK12 activity assays; RNA-seq after CDK12 inhibition; BRAF/RAS mutant cell line analysis; CDK12 inhibitor treatment; synergy assays with AP-1/NF-κB pathway inhibitors Nature communications Medium 36309522
2023 CDK12/CDK13 activity promotes the interaction of SF3B1 with RNAPII phosphorylated on Ser2; CDK12/13 inhibition disrupts SF3B1 association with chromatin and recruitment to 3' splice sites of promoter-proximal introns with weak splice sites, causing selective intron retention. THZ531 CDK12/13 inhibition; nascent transcript analysis; ChIP for SF3B1; Co-IP for SF3B1-RNAPII interaction; cell viability and cell cycle assays Nucleic acids research High 37026485
2023 CDK12 phosphorylates LEO1 (a PAF1 complex subunit); LEO1 phosphorylation promotes PAF1C association with elongating RNAPII and processive transcription elongation; LEO1 is dephosphorylated by the Integrator-PP2A complex (INTAC), and INTAC depletion promotes PAF1C association with RNAPII. Chemical genetic and phosphoproteomic screening; in vitro kinase assay; ChIP-seq for PAF1C and RNAPII; phospho-site mutagenesis (alanine substitution); Co-IP for INTAC-LEO1 interaction Science advances High 37205756
2023 SR-4835 (CDK12 inhibitor) acts as a molecular glue that promotes DDB1 interaction with the CDK12-cyclin K complex, leading to proteasomal degradation of cyclin K via the CUL4-RBX1-DDB1 ubiquitin ligase; the benzimidazole side-chain of SR-4835 is critical for molecular glue activity. Loss-of-function genetic screening; Co-IP of DDB1 with CDK12-cyclin K; proteasome inhibitor rescue; SAR analysis; docking studies Cell death discovery Medium 38104154
2024 CDK12 inactivation in prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration; CDK12 loss mediates genomic instability by inducing transcription-replication conflicts; CDK12-mutant cancer models are sensitive to inhibition or degradation of paralog kinase CDK13. Conditional Cdk12 ablation in murine prostate epithelium; CRISPR-based allograft screen; prostate organoids; transcription-replication conflict assays; CDK13 inhibitor/degrader treatment; patient-derived xenografts Cell reports. Medicine High 39368479
2024 CDK12 is recruited at damaged genes by PARP-dependent DDR signaling and elongation-competent RNAPII to repress transcription of those genes; CDK12 loss or inhibition leads to DDR-resistant transcription at damaged loci and exacerbates transcription-replication conflicts in MYC-overexpressing cells, accumulating double-strand breaks between co-directional early-replicating regions and transcribed genes. CDK12 ChIP at damaged genes; CDK12 KO/inhibition with DDR assays; MYC overexpression combined with CDK12 loss; DNA fiber assay for TRCs; γH2AX foci Nature communications High 39155303
2024 CDK12/13 degradation by PROTAC YJ1206 triggers gene-length-dependent transcriptional elongation defects and DNA damage; degradation also activates the AKT pathway, creating a synthetic lethal interaction with AKT pathway inhibitors in prostate cancer models. PROTAC CDK12/13 degrader (YJ1206/YJ9069); RNA-seq; phosphorylation pathway arrays; CDK12/13 genetic knockdown; in vivo xenograft models; synthetic lethality combination assays Cell reports. Medicine Medium 39353441
2022 THOC5 interacts with CDK12 in slow RNAPII cells; CDK12/THOC5 interaction promotes CDK12 recruitment to R-loops in a THOC6-dependent manner; THOC5 depletion decreases transcription elongation rates. Co-immunoprecipitation of THOC5 with CDK12; elongation rate measurement in vivo; ChIP for CDK12 at R-loops; THOC5 depletion iScience Medium 36590164
2020 CDK12 inhibition reduces DMPK mutant repeat expansion RNA levels and nuclear foci in myotonic dystrophy type 1 cells; CDK12 protein is elevated in DM1 cell lines and patient muscle biopsies; chemoproteomics identified CDK12 as the druggable target of small-molecule foci-clearing compounds. Chemoproteomics target identification; CDK12 inhibitor treatment; nuclear foci quantification; mouse model (HSALR) treatment with in vivo splicing and myotonia readouts Science translational medicine Medium 32350131
2024 Dual-site molecular glue LL-K12-18 enhances CDK12-DDB1 interaction at both the PPI region and its dynamic surroundings, leading to more efficient cyclin K degradation and stronger inhibition of gene transcription and tumor cell proliferation compared to single-site molecular glues. Molecular dynamics simulations guiding inhibitor design; CDK12-DDB1 Co-IP; cyclin K degradation assay; cell proliferation assay; structural analysis Nature communications Medium 39090085
2024 CDK12-DDB1 molecular glue degraders of CDK12/13 and BRD4 can be rationally designed by appending hydrophobic aromatic rings or double bonds to existing CDK12/13 dual inhibitors, which recruits DDB1 and enables proteasomal degradation. Structure-guided design of molecular glue degraders; Co-IP of DDB1 with CDK12; proteasomal degradation assays; cell proliferation assays Angewandte Chemie Medium 40626960
2019 CDK12 catalytic activity is required for expression of genes in the ErbB-PI3K-AKT and WNT signaling cascades, promoting breast cancer stem cell self-renewal and trastuzumab resistance. CDK12 kinase-dead mutant expression; RNA-seq; sphere formation assay; xenograft tumor-initiation assay; trastuzumab sensitivity assay EMBO reports Medium 31468695
2022 CDK12 nuclear import is mediated by TNPO1. siRNA knockdown of TNPO1 with CDK12 localization readout; Co-IP Journal of immunology research Low 33628849
2022 CDK12 phosphorylates MBNL1 to regulate vasculogenic mimicry in glioblastoma cells; BUD13 enhances CDK12 mRNA stability through m6A methylation, and CDK12 in turn phosphorylates MBNL1. BUD13/CDK12 knockdown and MBNL1 overexpression; Co-IP; western blot for MBNL1 phosphorylation; tube formation assay for vasculogenic mimicry; in vivo subcutaneous xenograft Cell death & disease Low 36463205
2024 CDK12 inhibition upregulates ATG7 and triggers autophagy through the AKT/FOXO3 pathway in colorectal cancer; CDK12 physically interacts with AKT; FOXO3 transcriptionally upregulates ATG7 when CDK12 is inhibited. CDK12 inhibitor treatment; Co-IP of CDK12 with AKT; ATG7 knockdown; FOXO3 ChIP or transcriptional assay; cell viability and autophagy assays Pharmacological research Low 38354870

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 480 29906450
2011 The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes & development 414 22012619
2010 CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes & development 327 20952539
2016 Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nature chemical biology 283 27571479
2018 CDK12 regulates DNA repair genes by suppressing intronic polyadenylation. Nature 251 30487607
2019 Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer. Cancer cell 239 31668947
2016 CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell reports 230 27880910
2019 CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation. Nature communications 212 30988284
2020 CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors. JCO precision oncology 188 32462107
2014 The structure and substrate specificity of human Cdk12/Cyclin K. Nature communications 167 24662513
2020 Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 166 32804079
2015 Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing. Molecular and cellular biology 165 25561469
2018 EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma. Cancer cell 134 29358035
2020 CDK13 cooperates with CDK12 to control global RNA polymerase II processivity. Science advances 133 32917631
2018 Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13. eLife 132 30422115
2017 CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion. Nucleic acids research 130 28334900
2015 Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex. Nucleic acids research 114 25712099
2001 CrkRS: a novel conserved Cdc2-related protein kinase that colocalises with SC35 speckles. Journal of cell science 113 11683387
2021 Discovery and resistance mechanism of a selective CDK12 degrader. Nature chemical biology 111 33753926
2006 Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation. Molecular and cellular biology 110 16537916
2012 Interaction of cyclin-dependent kinase 12/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymerase II. Molecular and cellular biology 105 22988298
2018 CDK12: an emerging therapeutic target for cancer. Journal of clinical pathology 103 30104286
2019 CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling. EMBO reports 101 31468695
2020 Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics. European urology 100 32317181
2012 Cyclin K goes with Cdk12 and Cdk13. Cell division 95 22512864
2019 CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma. Gut 92 31519701
2019 CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes. EMBO reports 84 31347271
2018 Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium. Transcription 84 30319007
2015 Cdk12 is essential for embryonic development and the maintenance of genomic stability. Cell death and differentiation 82 26658019
2020 CDK12 globally stimulates RNA polymerase II transcription elongation and carboxyl-terminal domain phosphorylation. Nucleic acids research 81 32805052
2020 Targeting CDK12 for Cancer Therapy: Function, Mechanism, and Drug Discovery. Cancer research 79 32958547
2020 CDK12-Mutated Prostate Cancer: Clinical Outcomes With Standard Therapies and Immune Checkpoint Blockade. JCO precision oncology 77 32671317
2020 CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer. Cancer letters 77 32941949
2021 BRCA2, ATM, and CDK12 Defects Differentially Shape Prostate Tumor Driver Genomics and Clinical Aggression. Clinical cancer research : an official journal of the American Association for Cancer Research 76 33414135
2021 Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell reports 70 34289372
2019 CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability. Genes & development 69 30819820
2020 Characterizing CDK12-Mutated Prostate Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 67 32988971
2017 The emerging roles of CDK12 in tumorigenesis. Cell division 66 29090014
2021 Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-Cyclin K complex and induce synthetic lethality with PARP inhibitor. European journal of medicinal chemistry 65 34864331
2022 Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13. Journal of medicinal chemistry 57 35938508
2018 Discovery of 3-Benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors. Journal of medicinal chemistry 57 30067358
2020 CDK12 and PAK2 as novel therapeutic targets for human gastric cancer. Theranostics 56 32483448
2019 Pan-Cancer Analysis of CDK12 Loss-of-Function Alterations and Their Association with the Focal Tandem-Duplicator Phenotype. The oncologist 56 31292271
2020 CDK12: A Potent Target and Biomarker for Human Cancer Therapy. Cells 52 32570740
2021 CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-tyrosine kinase inhibitor via suppressing PI3K/AKT. European journal of cancer (Oxford, England : 1990) 46 33429148
2018 Structure-Based Design of Selective Noncovalent CDK12 Inhibitors. ChemMedChem 45 29266803
2016 Role and therapeutic potential of CDK12 in human cancers. Cancer treatment reviews 44 27662623
2017 Residual Cdk1/2 activity after DNA damage promotes senescence. Aging cell 41 28345297
2021 CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer. Cell death & disease 40 34315855
2022 CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer. Nature communications 39 35550508
2020 The promise and current status of CDK12/13 inhibition for the treatment of cancer. Future medicinal chemistry 39 33295810
2023 Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids. Journal of experimental & clinical cancer research : CR 38 37202753
2019 Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma. The Journal of clinical investigation 37 31498151
2016 Cdk12 Is A Gene-Selective RNA Polymerase II Kinase That Regulates a Subset of the Transcriptome, Including Nrf2 Target Genes. Scientific reports 37 26911346
2015 Engineering an analog-sensitive CDK12 cell line using CRISPR/Cas. Biochimica et biophysica acta 37 26189575
2022 Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer. Cancer research 34 35857807
2022 CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma. Nature communications 34 36309522
2014 Bisphenol A exerts estrogenic effects by modulating CDK1/2 and p38 MAP kinase activity. Bioscience, biotechnology, and biochemistry 34 25130739
2020 CDK12: cellular functions and therapeutic potential of versatile player in cancer. NAR cancer 32 34316683
2018 CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling. Science signaling 32 30065029
2020 CDK12 Promotes Breast Cancer Progression and Maintains Stemness by Activating c-myc/β -catenin Signaling. Current cancer drug targets 31 31744448
2019 Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma. Biochemical and biophysical research communications 31 31615655
2024 CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13. Cell reports. Medicine 29 39368479
2020 CDK12: a potential therapeutic target in cancer. Drug discovery today 28 33038524
2014 Cdk12 and Cdk13 regulate axonal elongation through a common signaling pathway that modulates Cdk5 expression. Experimental neurology 28 24999027
2023 CDK12/13 promote splicing of proximal introns by enhancing the interaction between RNA polymerase II and the splicing factor SF3B1. Nucleic acids research 27 37026485
2020 Long Non-Coding RNA UCA1 Modulates Paclitaxel Resistance in Breast Cancer via miR-613/CDK12 Axis. Cancer management and research 27 32425595
2019 Expression pattern of CDK12 protein in gastric cancer and its positive correlation with CD8+ cell density and CCL12 expression. International journal of medical sciences 27 31523177
2023 The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma. Cell death discovery 26 38104154
2017 BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 25 29025359
2023 CDK12 and Integrator-PP2A complex modulates LEO1 phosphorylation for processive transcription elongation. Science advances 24 37205756
2022 CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer. Clinical and translational medicine 23 36254394
2017 Cdk12 Regulates Neurogenesis and Late-Arising Neuronal Migration in the Developing Cerebral Cortex. Cerebral cortex (New York, N.Y. : 1991) 23 27073218
2024 Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition. Cell reports. Medicine 22 39353441
2024 Synthetic Lethal Targeting of CDK12-Deficient Prostate Cancer with PARP Inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 21 39321214
2023 Discovery of a novel dual-target inhibitor of CDK12 and PARP1 that induces synthetic lethality for treatment of triple-negative breast cancer. European journal of medicinal chemistry 21 37478560
2024 CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts. Nature communications 20 39155303
2022 CDK12 regulates co-transcriptional splicing and RNA turnover in human cells. iScience 20 36111258
2021 Differential treatment outcomes in BRCA1/2-, CDK12-, and ATM-mutated metastatic castration-resistant prostate cancer. Cancer 20 33690902
2022 The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells. Cell death & disease 19 36463205
2019 Loss of MAP3K7 Sensitizes Prostate Cancer Cells to CDK1/2 Inhibition and DNA Damage by Disrupting Homologous Recombination. Molecular cancer research : MCR 19 31300540
2015 Heterochromatin remodeling by CDK12 contributes to learning in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 19 26508632
2022 Current progress and novel strategies that target CDK12 for drug discovery. European journal of medicinal chemistry 18 35868123
2020 CDK12 promotes papillary thyroid cancer progression through regulating the c-myc/β-catenin pathway. Journal of Cancer 18 32489449
2024 CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer. Pharmacological research 17 38354870
2020 CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model. Science translational medicine 17 32350131
2019 Quantitative Mass Spectrometry to Interrogate Proteomic Heterogeneity in Metastatic Lung Adenocarcinoma and Validate a Novel Somatic Mutation CDK12-G879V. Molecular & cellular proteomics : MCP 17 30617155
2021 CDK12 Promotes Cervical Cancer Progression through Enhancing Macrophage Infiltration. Journal of immunology research 16 33628849
2024 CDK12 regulates angiogenesis of advanced prostate cancer by IGFBP3. International journal of oncology 15 38186306
2020 CDK12 Deficiency and the Immune Microenvironment in Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 15 33199495
2024 Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex. Nature communications 14 39090085
2024 Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader. Journal of medicinal chemistry 14 39388374
2023 Inhibition of the Cyclin K-CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate cancer. International journal of cancer 14 37916780
2022 THOC5 complexes with DDX5, DDX17, and CDK12 to regulate R loop structures and transcription elongation rate. iScience 14 36590164
2025 Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders. Angewandte Chemie (International ed. in English) 13 40626960
2023 Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13. Proceedings of the National Academy of Sciences of the United States of America 13 37695916
2022 Transcription-associated cyclin-dependent kinase 12 (CDK12) as a potential target for cancer therapy. Biochimica et biophysica acta. Reviews on cancer 13 36460141
2020 Low expression of CDK12 in gastric cancer is correlated with advanced stage and poor outcome. Pathology, research and practice 13 32534699
2022 Response and resistance to CDK12 inhibition in aggressive B-cell lymphomas. Haematologica 12 34162179
2009 CRK7 modifies the MAPK pathway and influences the response to endocrine therapy. Carcinogenesis 12 19651820

Missed literature

Know a paper Affinage missed for CDK12? Flag it for the maintainers and the community.

No submissions yet.