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Showing XAB2 — NTC90 is a alias.

XAB2

Pre-mRNA-splicing factor SYF1 · UniProt Q9HCS7

Length
855 aa
Mass
100.0 kDa
Annotated
2026-06-11
25 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

XAB2 is a tetratricopeptide-repeat protein that couples pre-mRNA splicing to genome maintenance and transcription, operating within a conserved multimeric complex comprising hAquarius, PRP19, CCDC16, ISY1, and PPIE (PMID:10944529, PMID:17981804). First identified through its physical association with XPA, CSA, CSB, and RNA polymerase II, XAB2 is selectively required for transcription-coupled repair and ongoing transcription but not global genome repair (PMID:10944529), a function essential for early development, as its loss causes preimplantation lethality in mice (PMID:15725628). As a splicing factor, XAB2 binds the core spliceosome and U4/U6 snRNAs and pre-mRNAs in vivo, and its yeast ortholog Ntc90 recruits the first-step factor Yju2 after spliceosome activation (PMID:19617314, PMID:34039990); loss of XAB2 produces widespread intron retention and, by depleting correctly spliced POLR2A mRNA, collapses global transcription and drives p53/p21-dependent senescence (PMID:31216022, PMID:34039990). In transcription-coupled nucleotide excision repair XAB2 behaves uniquely among NER factors: rather than accumulating at damage, it becomes more mobile and is released from R-loops and from its CSA and XPG partners upon lesion induction, an event needed for timely resolution of stalled RNAP2 (PMID:35880862); consistent with this, XAB2 forms a trimeric complex with ERCC1-XPF and XPG that binds RNA:DNA hybrids, and transcription-blocking lesions trigger its release from RNA targets (PMID:34039990). At double-strand breaks XAB2 promotes end resection and homologous recombination, supporting CtIP phosphorylation, BRCA1 and RAD51 focus formation, and Ku eviction from single-ended breaks through an ATM-independent pathway (PMID:27084940, PMID:34500463). XAB2 additionally acts as a transcriptional regulator, activating CENPE to enable mitotic progression and, when stabilized by USP10-mediated deubiquitination at K593, driving ANXA2 expression and DNA damage tolerance (PMID:27735937, PMID:40069750); it also associates with a RARα/HDAC3 corepressor complex to restrain retinoic-acid-induced differentiation (PMID:17283134).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 High

    Established XAB2 as a dedicated transcription-coupled repair factor by linking it physically to the NER/TCR machinery and showing its functional requirement in living cells.

    Evidence Yeast two-hybrid, reciprocal Co-IP with XPA/CSA/CSB/RNAP II, and anti-XAB2 antibody microinjection with TCR vs GGR assays in fibroblasts

    PMID:10944529

    Open questions at the time
    • Did not define the biochemical step within TCR at which XAB2 acts
    • No structural basis for the interactions
  2. 2005 High

    Demonstrated that XAB2 is indispensable for organismal viability, placing its function at an essential developmental checkpoint.

    Evidence Two independent XAB2 knockout alleles in mice with embryo developmental staging

    PMID:15725628

    Open questions at the time
    • Lethality cause (splicing vs repair vs transcription defect) not resolved
    • No conditional/tissue-specific analysis
  3. 2007 High

    Defined XAB2 as a stable subunit of a multimeric splicing-factor complex whose composition is remodeled by DNA damage, unifying its splicing and repair activities.

    Evidence Multistep chromatographic purification with MS identification, siRNA knockdown (UV sensitivity, RNA synthesis recovery), Co-IP after damage

    PMID:17981804

    Open questions at the time
    • Stoichiometry and architecture of the complex unknown
    • Mechanism of damage-induced remodeling undefined
  4. 2007 Medium

    Extended XAB2 function to transcriptional corepression by linking it to a RARα/HDAC3 complex controlling differentiation.

    Evidence Nuclear Co-IP, siRNA knockdown and overexpression with ATRA-induced differentiation assays in HL60 and IMR-32 cells

    PMID:17283134

    Open questions at the time
    • Single-lab finding without reciprocal validation of the corepressor complex
    • Direct vs indirect role in RAR target repression not established
  5. 2009 High

    Assigned a precise splicing-mechanistic role to the XAB2 ortholog, showing it recruits a first-step factor after spliceosome activation rather than driving activation itself.

    Evidence Biochemical pulldown, genetic complementation, and spliceosome assembly assays of yeast Ntc90/SYF1

    PMID:19617314

    Open questions at the time
    • Conservation of the Yju2-recruitment role in human XAB2 not directly tested
    • Does not connect splicing step to the repair functions
  6. 2016 High

    Showed XAB2 promotes the end-resection step of homologous recombination, expanding its genome-maintenance role beyond TCR.

    Evidence siRNA knockdown with DSB repair/resection assays, RAD51/BRCA1/γH2AX IRIF, domain mapping, Co-IP, and live imaging

    PMID:27084940

    Open questions at the time
    • Whether resection role is a direct activity or a splicing-dependent consequence not separated
    • Molecular target of XAB2 at break sites unidentified
  7. 2016 High

    Identified XAB2 as a transcriptional activator of CENPE required for mitotic progression, broadening its function to cell-cycle control.

    Evidence ChIP and promoter-deletion mapping, luciferase reporter, live imaging, flow cytometry, and CENPE epistasis

    PMID:27735937

    Open questions at the time
    • Whether CENPE activation reflects direct DNA binding or splicing-mediated regulation unclear
    • No defined DNA-binding domain for promoter engagement
  8. 2019 High

    Mechanistically linked XAB2's splicing activity to global transcription by showing it ensures correct POLR2A splicing, with failure driving senescence.

    Evidence RNA-seq, TMT proteomics, Co-IP, SNW1 domain mapping (TPR 2–4, 11), and POLR2A re-expression rescue of senescence

    PMID:31216022

    Open questions at the time
    • Full set of XAB2-dependent transcripts not enumerated
    • Relationship between POLR2A loss and repair phenotypes not dissected
  9. 2021 High

    Connected XAB2's RNA-binding/splicing function to R-loop suppression and NER-endonuclease association, providing a substrate-level basis for its genome protection.

    Evidence In vivo biotinylation pulldown, RNA-IP of U4/U6 snRNAs and pre-mRNAs, DRIP, RNA:DNA hybrid binding, and Csb-mutant mouse models

    PMID:34039990

    Open questions at the time
    • Functional consequence of the XAB2–ERCC1-XPF–XPG trimeric complex at R-loops not fully defined
    • How lesion sensing triggers RNA release unknown
  10. 2021 High

    Showed XAB2 evicts Ku from single-ended DSBs through an ATM-independent pathway parallel to CtIP-MRE11, refining its HR mechanism.

    Evidence Ku retention/IRIF assays, RAD51 foci, ATM-inhibition epistasis, RAD51/RAD52 overexpression rescue, and synthetic lethality with RAD52 inhibition

    PMID:34500463

    Open questions at the time
    • Direct biochemical activity of XAB2 in Ku displacement not reconstituted
    • How the ATM-independent branch is regulated unknown
  11. 2022 High

    Revealed XAB2's distinctive TC-NER mechanism: it is released rather than recruited at damage, with its mobilization required for resolving stalled RNAP2.

    Evidence FRAP live imaging, local UV-C/laser micro-irradiation, Co-IP with CSA/XPG/R-loops, and TC-NER reporter assays

    PMID:35880862

    Open questions at the time
    • Molecular trigger and machinery driving XAB2 release not defined
    • How released XAB2 promotes downstream repair steps unclear
  12. 2025 High

    Identified post-translational control of XAB2 stability by USP10 and a downstream ANXA2 transcriptional program promoting chemoresistance.

    Evidence Co-IP, ubiquitination-site MS and K593 mutagenesis, deubiquitinase assay, ChIP-seq/ChIP-qPCR, luciferase, and RNA-seq in colorectal cancer cells

    PMID:40069750

    Open questions at the time
    • Single-lab finding in colorectal cancer context
    • Generality of USP10–XAB2–ANXA2 axis beyond oxaliplatin resistance untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How XAB2's splicing, transcription, R-loop, TC-NER, and HR functions are mechanistically partitioned versus interdependent remains unresolved.
  • No structure of XAB2 or its complexes
  • No separation-of-function alleles distinguishing splicing from repair roles
  • Direct DNA-binding capacity for promoter activation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-8953854 Metabolism of RNA 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1640170 Cell Cycle 1
Partners
CSAERCC1ISY1PRP19SNW1USP10XPAXPG
Complex memberships
RARα/HDAC3 corepressor complexXAB2 complex (hAquarius/XAB2/PRP19/CCDC16/ISY1/PPIE)XAB2-ERCC1-XPF-XPG trimeric complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 XAB2 (XPA-binding protein 2) physically interacts with XPA, CSA, CSB, and RNA polymerase II, as demonstrated by immunoprecipitation. Microinjection of anti-XAB2 antibodies into living fibroblasts inhibited transcription-coupled repair (TCR) and transcription but NOT global genome repair, establishing XAB2 as a specific component of the TCR pathway. Yeast two-hybrid (initial identification), co-immunoprecipitation, antibody microinjection into living fibroblasts with TCR and GGR assays The Journal of biological chemistry High 10944529
2007 XAB2 exists as a multimeric protein complex (XAB2 complex) consisting of hAquarius, XAB2, hPRP19, CCDC16, hISY1, and PPIE, all of which are pre-mRNA splicing factors. siRNA knockdown of XAB2 caused UV hypersensitivity and decreased RNA synthesis recovery. Enhanced interaction of XAB2 with RNA polymerase IIo or XPA was observed after DNA damage, indicating a DNA damage-responsive remodeling of the complex. Biochemical purification (multistep chromatography), mass spectrometry identification of complex components, siRNA knockdown, co-immunoprecipitation after DNA damage The Journal of biological chemistry High 17981804
2005 Homozygous deletion of XAB2 in mice results in preimplantation lethality: embryos survive to morula stage but fail to develop to blastocyst, demonstrating that XAB2 is essential for early mouse embryogenesis. Gene targeting/knockout in mice; embryo staging by developmental analysis DNA repair High 15725628
2007 XAB2 associates with retinoic acid receptor alpha (RARα) and histone deacetylase 3 (HDAC3) in the nucleus, forming part of a RAR corepressor complex. Overexpression of XAB2 inhibited ATRA-induced cellular differentiation, while siRNA knockdown of XAB2 enhanced ATRA-induced differentiation in HL60 and overcame ATRA resistance in IMR-32 neuroblastoma cells. Co-immunoprecipitation (nuclear fraction), siRNA knockdown, overexpression, cellular differentiation assays Cancer research Medium 17283134
2009 The yeast ortholog Ntc90 (NTC90/SYF1) interacts with multiple NTC components (Ntc31, Ntc30, Ntc20) through distinct regions but is NOT required for spliceosome activation; instead, Ntc90 is specifically required for recruiting the first-step splicing factor Yju2 after spliceosome activation. Biochemical pulldown, genetic complementation, spliceosome assembly assays in yeast RNA (New York, N.Y.) High 19617314
2016 XAB2 promotes the end resection step of homologous recombination (HR) at chromosomal double-strand breaks. XAB2 depletion impairs: DSB repair via end resection-dependent HR pathways, CtIP hyperphosphorylation, BRCA1 IRIF, RAD51 recruitment to IRIF, and histone acetylation events linked to HR. This function requires complex formation with ISY1 and PRP19. The XAB2–ISY1–PRP19 complex localizes to interchromatin granule-like structures adjacent to (but not coincident with) γH2AX foci. siRNA knockdown, DSB repair assays (chromosomal), end resection assays, IRIF (RAD51, BRCA1, γH2AX) by immunofluorescence, truncation/domain mutagenesis, co-immunoprecipitation, live cell imaging Nucleic acids research High 27084940
2016 XAB2 regulates mitotic cell cycle progression by transcriptionally activating CENPE. XAB2 depletion causes G2/M arrest at prophase/prometaphase, chromosome misalignment, segregation defects, and mitotic catastrophe. XAB2 binds to the CENPE promoter (ChIP assay) and its overexpression increases CENPE promoter-driven luciferase activity. CENPE knockdown phenocopies XAB2 loss, and epistasis shows no additive effect. siRNA knockdown, live cell imaging, flow cytometry, microarray, luciferase reporter assay, ChIP assay, promoter deletion mapping Cell death & disease High 27735937
2019 XAB2 depletion causes intron retention and loss of POLR2A (largest subunit of RNA Pol II) mRNA and protein, impairing global transcription and inducing cellular senescence via p53/p21 upregulation. Re-expression of POLR2A after XAB2 depletion rescues senescence. XAB2 physically associates with spliceosome components required for POLR2A expression, and domain mapping shows that TPR motifs 2–4 and 11 of XAB2 interact with SNW1 and are critical for this function. siRNA knockdown, RNA-seq, TMT-based quantitative proteomics, co-immunoprecipitation, luciferase/splicing assays, domain truncation mapping, senescence assays (SA-β-gal, p53/p21 western blot), rescue experiments Nucleic acids research High 31216022
2021 XAB2 interacts with the core spliceosome and binds spliceosomal U4 and U6 snRNAs as well as pre-mRNAs in vivo. XAB2 depletion causes aberrant intron retention, R-loop formation, and DNA damage. XAB2 interacts with ERCC1-XPF and XPG endonucleases in a complex outside nucleotide excision repair, and this trimeric complex binds RNA:DNA hybrids under R-loop-favoring conditions. Transcription-blocking DNA lesions (illudin S treatment; Csb-mutant livers) trigger release of XAB2 from all RNA targets tested. In vivo biotinylation-tagging/streptavidin pulldown in mice, RNA immunoprecipitation (snRNA and pre-mRNA), co-immunoprecipitation, R-loop detection (DRIP assay), RNA:DNA hybrid binding assay, genetic mouse models (Csbm/m) Nature communications High 34039990
2021 XAB2 promotes Ku eviction from single-ended DNA double-strand breaks (seDSBs) via a pathway parallel to and independent of the ATM-CtIP-MRE11 axis. XAB2 depletion causes Ku retention at seDSBs induced by temozolomide and camptothecin, unproductive RAD51-ssDNA associations, increased NHEJ in S/G2, and genetic instability. Overexpression of RAD51 or RAD52 rescues XAB2-deficient HR defects, and XAB2 loss is synthetically lethal with RAD52 inhibition. siRNA knockdown, Ku retention/IRIF assays, RAD51 focus assays, genetic epistasis (ATM inhibition + XAB2 depletion), overexpression rescue, synthetic lethality assay with RAD52 inhibitor Nucleic acids research High 34500463
2022 XAB2 is specifically required for Transcription-Coupled Nucleotide Excision Repair (TC-NER) for RNAP2-transcribed genes. Unlike all other studied NER proteins, XAB2 does NOT accumulate at UV-C damage sites but instead becomes MORE mobile after DNA damage, with mobility restored upon repair completion. XAB2 is released from R-loops and from CSA and XPG partners upon DNA damage induction. In the absence of XAB2, RNAP2 is blocked longer on UV lesions. XAB2 also retains RNAP2 on its substrate in the absence of DNA damage. Live-cell fluorescence recovery after photobleaching (FRAP), local UV-C damage/laser micro-irradiation, co-immunoprecipitation (XAB2 with CSA, XPG, R-loops), TC-NER reporter assays, siRNA knockdown eLife High 35880862
2025 USP10 deubiquitinates XAB2 at K48-linked polyubiquitination site K593, preventing its proteasomal degradation and thus stabilizing XAB2 protein levels in response to oxaliplatin treatment. Stabilized XAB2 binds the ANXA2 promoter and upregulates ANXA2 transcription, promoting DNA damage repair and oxaliplatin resistance in colorectal cancer cells. Co-immunoprecipitation, ubiquitination site mass spectrometry, ubiquitin assay, dual-luciferase reporter assay, ChIP-qPCR, ChIP-seq, RNA-seq, site-directed mutagenesis (K593), Western blot Journal of experimental & clinical cancer research : CR High 40069750

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 XAB2, a novel tetratricopeptide repeat protein involved in transcription-coupled DNA repair and transcription. The Journal of biological chemistry 115 10944529
2007 Isolation of XAB2 complex involved in pre-mRNA splicing, transcription, and transcription-coupled repair. The Journal of biological chemistry 87 17981804
2022 Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients With Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A). Journal of clinical oncology : official journal of the American Society of Clinical Oncology 82 35442713
2016 A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157. Clinical cancer research : an official journal of the American Association for Cancer Research 61 27932416
2021 The splicing factor XAB2 interacts with ERCC1-XPF and XPG for R-loop processing. Nature communications 47 34039990
2005 Disruption of mouse XAB2 gene involved in pre-mRNA splicing, transcription and transcription-coupled DNA repair results in preimplantation lethality. DNA repair 36 15725628
2016 XAB2 functions in mitotic cell cycle progression via transcriptional regulation of CENPE. Cell death & disease 31 27735937
2021 A multi-center, single-arm, phase Ib study of pembrolizumab (MK-3475) in combination with chemotherapy for patients with advanced colorectal cancer: HCRN GI14-186. Cancer immunology, immunotherapy : CII 29 34160684
2025 USP10/XAB2/ANXA2 axis promotes DNA damage repair to enhance chemoresistance to oxaliplatin in colorectal cancer. Journal of experimental & clinical cancer research : CR 28 40069750
2019 Enhanced azo dye biodegradation performance and halotolerance of Candida tropicalis SYF-1 by static magnetic field (SMF). Bioresource technology 28 31669874
2023 Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B). Journal for immunotherapy of cancer 27 36948504
2019 XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence. Nucleic acids research 25 31216022
2016 Tetratricopeptide repeat factor XAB2 mediates the end resection step of homologous recombination. Nucleic acids research 25 27084940
2007 Knockdown of XAB2 enhances all-trans retinoic acid-induced cellular differentiation in all-trans retinoic acid-sensitive and -resistant cancer cells. Cancer research 17 17283134
2009 Ntc90 is required for recruiting first step factor Yju2 but not for spliceosome activation. RNA (New York, N.Y.) 16 19617314
2021 XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase. Nucleic acids research 13 34500463
2015 XAB2 tagSNPs contribute to non-small cell lung cancer susceptibility in Chinese population. BMC cancer 12 26228655
2023 Phase II randomised, double-blind study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients (HCRN GI14-198). European journal of cancer (Oxford, England : 1990) 11 37268519
2022 XAB2 dynamics during DNA damage-dependent transcription inhibition. eLife 11 35880862
2024 Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A). Journal for immunotherapy of cancer 6 38604810
2018 The Entamoeba histolytica Syf1 Homolog Is Involved in the Splicing of AG-Dependent and AG-Independent Transcripts. Frontiers in cellular and infection microbiology 4 30038900
2021 XAB2 TagSNP Is Associated with the Risk of Gastric Cancer in Chinese Population: A Case-Control Study. International journal of environmental research and public health 3 33557438
2023 Phase 2 Trial of Nivolumab and Ramucirumab for Relapsed Mesothelioma: HCRN-LUN15-299. JTO clinical and research reports 2 38046376
2026 XAB2: a link between RNA metabolism, DNA damage repair, and human health. Transcription 0 41848795
2026 Dissecting the Tumor Microenvironment to Identify Biomarkers of Outcome to Anti-PD-1 Therapy in Clear Cell Renal Cell Carcinoma: analyses of the HCRN GU16-260 trial. Clinical cancer research : an official journal of the American Association for Cancer Research 0 42149133

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