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BTAF1: a key regulator of DNA end resection and predictor of chemotherapy sensitivity in gastric cancer

Cell Death & Differentiation (2026)Cite this article

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Abstract

BTAF1, an ATP-dependent remodeler of the TBP-DNA complex, is frequently mutated in gastric cancer. However, its role in DNA repair and therapeutic relevance remains largely undefined. Here, we show that BTAF1 knockout leads to accumulation of double-strand breaks (DSBs) by impairing DNA end-resection process of homologous recombination (HR) repair, thereby sensitizing cells to genotoxic agents both in vitro and in vivo. Mechanistically, BTAF1 prevents ubiquitin-mediated degradation of MRE11, maintaining its protein stability, promoting DNA end resection and HR, and consequently enhancing cellular resistance to DNA-damaging stress. Notably, the interaction between BTAF1 and MRE11 is dynamically regulated by PARP1-mediated PARylation of BTAF1 during the DNA damage response. Loss of BTAF1 also increases chemosensitivity in gastric cancer xenograft and organoid models. Clinically, high BTAF1 expression correlates with poor prognosis in gastric cancer patients receiving neoadjuvant chemotherapy. Collectively, our findings identify BTAF1 as a critical regulator of HR repair through stabilization of MRE11 and propose BTAF1 as a potential biomarker for predicting response to genotoxic chemotherapy.

BTAF1 is frequently mutated in gastric cancer, yet its role in DNA repair remains unclear. BTAF1 promotes homologous recombination and chemoresistance in gastric cancer by stabilizing MRE11. BTAF1 loss impairs DNA end resection, sensitizing cells to genotoxic agents. The BTAF1-MRE11 interaction is regulated by PARP1 mediated PARylation.

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Fig. 1: BTAF1 deficiency impairs HR repair and induces DNA damage.
Fig. 2: BTAF1 interacts with MRE11 to facilitate HR repair through promoting DNA end resection.
Fig. 3: BTAF1 prevents MRE11 degradation via the ubiquitin–proteasome pathway.
Fig. 4: DNA damage-induced BTAF1 dePARylation releases MRE11 for DNA repair.
Fig. 5: PARylation of BTAF1 at five conserved residues is critical for DNA damage response.
Fig. 6: BTAF1 as a potential sensitivity predictor for platinum-based chemotherapy.
Fig. 7: BTAF1 as a potential sensitivity predictor for platinum-based chemotherapy.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Uncropped original western blot images are provided in the Supplementary Information.

References

  1. Brown JS, O’Carrigan B, Jackson SP, Yap TA. Targeting DNA repair in cancer beyond PARP inhibitors. Cancer Discov. 2017;7:20–37.

    Article  PubMed  CAS  Google Scholar 

  2. Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11:220–8.

    Article  PubMed  CAS  Google Scholar 

  3. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Chang HH, Pannunzio NR, Adachi N, Lieber MR. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol. 2017;18:495–506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Chapman JR, Taylor MR, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012;47:497–510.

    Article  PubMed  CAS  Google Scholar 

  6. Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science. 2017;355:1152–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Groelly FJ, Fawkes M, Dagg RA, Blackford AN, Tarsounas M. Targeting DNA damage response pathways in cancer. Nat Rev Cancer. 2023;23:78–94.

    Article  PubMed  CAS  Google Scholar 

  8. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12:587–98.

    Article  PubMed  CAS  Google Scholar 

  9. Gogola E, Rottenberg S, Jonkers J. Resistance to PARP inhibitors: lessons from preclinical models of BRCA-associated cancer. Annu Rev Cancer Biol. 2019;3:235–54.

    Article  Google Scholar 

  10. Raderschall E, Stout K, Freier S, Suckow V, Schweiger S, Haaf T. Elevated levels of Rad51 recombination protein in tumor cells. Cancer Res. 2002;62:219–25.

    PubMed  CAS  Google Scholar 

  11. Ma CX, Janetka JW, Piwnica-Worms H. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends Mol Med. 2011;17:88–96.

    Article  PubMed  CAS  Google Scholar 

  12. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31:1869–83.

    Article  PubMed  CAS  Google Scholar 

  13. Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009;9:338–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Pilié PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019;16:81–104.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bian L, Meng Y, Zhang M, Li D. MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment. Mol Cancer. 2019;18:169.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Huertas P, Jackson SP. Human CtIP mediates cell cycle control of DNA end resection and double strand break repair. J Biol Chem. 2009;284:9558–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Anand R, Ranjha L, Cannavo E, Cejka P. Phosphorylated CtIP functions as a co-factor of the MRE11-RAD50-NBS1 endonuclease in DNA end resection. Mol Cell. 2016;64:940–50.

    Article  PubMed  CAS  Google Scholar 

  18. Stracker TH, Petrini JH. The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol. 2011;12:90–103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Garcia V, Phelps SE, Gray S, Neale MJ. Bidirectional resection of DNA double-strand breaks by Mre11 and Exo1. Nature. 2011;479:241–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Zhang T, Yang H, Zhou Z, Bai Y, Wang J, Wang W. Crosstalk between SUMOylation and ubiquitylation controls DNA end resection by maintaining MRE11 homeostasis on chromatin. Nat Commun. 2022;13:5133.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Cejka P, Symington LS. DNA end resection: mechanism and control. Annu Rev Genet. 2021;55:285–307.

    Article  PubMed  CAS  Google Scholar 

  22. Jachimowicz RD, Beleggia F, Isensee J, Velpula BB, Goergens J, Bustos MA, et al. UBQLN4 represses homologous recombination and is overexpressed in aggressive tumors. Cell. 2019;176:505–19.e22.

    Article  PubMed  CAS  Google Scholar 

  23. Belmonte-Fernández A, Herrero-Ruíz J, Galindo-Moreno M, Limón-Mortés MC, Mora-Santos M, Sáez C, et al. Cisplatin-induced cell death increases the degradation of the MRE11-RAD50-NBS1 complex through the autophagy/lysosomal pathway. Cell Death Differ. 2023;30:488–99.

    Article  PubMed  Google Scholar 

  24. Nicholson J, Jevons SJ, Groselj B, Ellermann S, Konietzny R, Kerr M, et al. E3 ligase cIAP2 mediates downregulation of MRE11 and radiosensitization in response to HDAC inhibition in bladder cancer. Cancer Res. 2017;77:3027–39.

    Article  PubMed  CAS  Google Scholar 

  25. Sanchez-Bailon M, Choi S, Dufficy E, Sharma K, McNee G, Gunnell E, et al. Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair. Nat Commun. 2021;12:6313.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Yu Z, Vogel G, Coulombe Y, Dubeau D, Spehalski E, Hébert J, et al. The MRE11 GAR motif regulates DNA double-strand break processing and ATR activation. Cell Res. 2012;22:305–20.

    Article  PubMed  CAS  Google Scholar 

  27. Chen Y, Wu J, Zhai L, Zhang T, Yin H, Gao H, et al. Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell. 2024;187:294–311.e21.

    Article  PubMed  CAS  Google Scholar 

  28. Zeng X, Zhao F, Cui G, Zhang Y, Deshpande RA, Chen Y, et al. METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma. Nat Cancer. 2022;3:1088–104.

    Article  PubMed  CAS  Google Scholar 

  29. Bai Y, Wang W, Li S, Zhan J, Li H, Zhao M, et al. C1QBP promotes homologous recombination by stabilizing MRE11 and controlling the assembly and activation of the MRE11/RAD50/NBS1 complex. Mol Cell. 2019;75:1299–1314.e6.

    Article  PubMed  CAS  Google Scholar 

  30. Liu W, Zheng M, Zhang R, Jiang Q, Du G, Wu Y, et al. RNF126-mediated MRE11 ubiquitination activates the DNA damage response and confers resistance of triple-negative breast cancer to radiotherapy. Adv Sci. 2023;10:2203884.

    Article  CAS  Google Scholar 

  31. Chicca JJ, Auble DT, Pugh BF. Cloning and biochemical characterization of TAF-172, a human homolog of yeast Mot1. Mol Cell Biol. 1998;18:1701–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Pereira LA, Klejman MP, Timmers HTM. Roles for BTAF1 and Mot1p in dynamics of TATA-binding protein and regulation of RNA polymerase II transcription. Gene. 2003;315:1–13.

    Article  PubMed  CAS  Google Scholar 

  33. Pereira LA, Klejman MP, Ruhlmann C, Kavelaars F, Oulad-Abdelghani M, Timmers HTM, et al. Molecular architecture of the basal transcription factor B-TFIID. J Biol Chem. 2004;279:21802–7.

    Article  PubMed  CAS  Google Scholar 

  34. Klejman MP, Zhao X, van Schaik FM, Herr W, Timmers HTM. Mutational analysis of BTAF1-TBP interaction: BTAF1 can rescue DNA-binding defective TBP mutants. Nucleic Acids Res. 2005;33:5426–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Butryn A, Schuller JM, Stoehr G, Runge-Wollmann P, Förster F, Auble DT, et al. Structural basis for recognition and remodeling of the TBP:DNA:NC2 complex by Mot1. eLife. 2015;4:e07432.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Cai MY, Hou JH, Rao HL, Luo RZ, Li M, Pei XQ, et al. High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. Mol Med. 2011;17:12–20.

    Article  PubMed  CAS  Google Scholar 

  37. Olivieri M, Cho T, Álvarez-Quilón A, Li K, Schellenberg MJ, Zimmermann M, et al. A genetic map of the response to DNA damage in human cells. Cell. 2020;182:481–96.e21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. van der Knaap JA, van den Boom V, Kuipers J, van Eijk MJ, van der Vliet PC, Timmers HTM. The gene for human TATA-binding-protein-associated factor (TAFII) 170: structure, promoter and chromosomal localization. Biochem J. 2000;345:521–7.

    Article  PubMed  PubMed Central  Google Scholar 

  39. van der Knaap JA, Borst JW, van der Vliet PC, Gentz R, Timmers HTM. Cloning of the cDNA for the TATA-binding protein-associated factorII170 subunit of transcription factor B-TFIID reveals homology to global transcription regulators in yeast and Drosophila. Proc Natl Acad Sci USA. 1997;94:11827–32.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Pereira LA, van der Knaap JA, van den Boom V, van den Heuvel FA, Timmers HTM. TAFII170 interacts with the concave surface of TATA-binding protein to inhibit its DNA binding activity. Mol Cell Biol. 2001;21:7523–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Li X, Heyer WD. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res. 2008;18:99–113.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol. 2017;18:610–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Slade D. PARP and PARG inhibitors in cancer treatment. Genes Dev. 2020;34:360–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Lo Monte M, Manelfi C, Gemei M, Corda D, Beccari AR. ADPredict: ADP-ribosylation site prediction based on physicochemical and structural descriptors. Bioinformatics. 2018;34:2566–74.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481:287–94.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the grants from the National Key R&D Program of China (No. 2021YFA1300201), the National Natural Science Foundation of China (grant No. 81972227, 82172646, 82202905 and 82373190), and Guangdong basic and applied basic research foundation (No. 2024A1515012828). The patient-derived GCOs was a kind gift from Prof. Xiaoxing Li (Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China).

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Author notes

  1. These authors contributed equally: Juan-Juan Xie, Ji-Liang Lin, Zhi-Cheng Xiang.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China

    Juan-Juan Xie, Ji-Liang Lin, Zhi-Cheng Xiang, Xiao-xia Cai, Run-Cong Nie, Peng Lin, Yi-Xin Yin, Jin-Ling Duan, Dan Xie & Mu-Yan Cai

  2. Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China

    Juan-Juan Xie

  3. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Zhi-Cheng Xiang, Chun-Hua Qu, Jin-Ling Duan, Dan Xie & Mu-Yan Cai

  4. Department of Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

    Run-Cong Nie & Peng Lin

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Contributions

Conceptualization, M-YC, DX, and J-JX; Methodology, J-JX, J-LD, J-LL and Z-CX; Software, J-JX, C-HQ, and X-XC; Investigation, R-CN, PL; Formal Analysis, Y-XY; Writing – Original Draft, J-JX, J-LD, Z-CX, and J-LL; Writing – Review & Editing, DX and M-YC; Funding Acquisition, DX, M-YC, J-LD and PL; Resources, DX and M-YC; Supervision, DX, M-YC and J-LD.

Corresponding authors

Correspondence to Jin-Ling Duan, Dan Xie or Mu-Yan Cai.

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Institutional Review Board approval (Sun Yat-sen University Cancer Center) the protocol (B2023-335-01) and informed consent were obtained prior to tissue acquisition and analysis. Animal ethics are listed in the Materials and Methods section.

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Supplemental Table 2 Mass spectrum data (Related to Figure 2E) (download CSV )

Supplemental Table 3 ADPredict score of amino residues in BTAF1 N-terminal (Related to Figure 5B) (download CSV )

Supplemental Table 4 Transcriptome sequencing data of HEK293T cells (download XLS )

Supplemental Table 5 Transcriptome sequencing data of HeLa cells (download XLS )

Supplementary material-Uncropped western blots (download PDF )

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Xie, JJ., Lin, JL., Xiang, ZC. et al. BTAF1: a key regulator of DNA end resection and predictor of chemotherapy sensitivity in gastric cancer. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01709-6

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