VGLL3 modulates chemosensitivity through promoting DNA double-strand break repair
Transcription cofactor vestigial-like 3 (VGLL3), as a master regulator of female-biased autoimmunity, also functions in tumor development, while the underlying mechanisms remain largely elusive. Here, we report that VGLL3 plays an important role in DNA damage response (DDR). VGLL3 can be recruited to damage sites in a PARylation-dependent manner. VGLL3 depletion impairs the accumulation of RNF8 and RAD51 at sites of DNA damage, leading to reduced homologous recombination efficiency and increased cellular sensitivity to chemotherapeutic drugs. Mechanistically, VGLL3 can prevent CtIP from KLHL15-mediated ubiquitination and degradation through competitive binding with KLHL15 and, meanwhile, stabilize MDC1 by limiting TRIP12-MDC1 but promoting USP7-MDC1 associations for optimal RNF8 signaling initiation. Consistently, VGLL3 depletion delays tumor development and sensitizes the xenografts to etoposide treatment. Overall, our results reveal an unexpected role of VGLL3 in DDR, which is distinct from its transcriptional cofactor function and not conserved among VGLL family members.
Authors
- Zhenzhen Fan (ORCID: https://orcid.org/0000-0002-3769-5286)
- Chuanchao Zhang (ORCID: https://orcid.org/0000-0003-0690-613X)
- Xiaolu Ma (ORCID: https://orcid.org/0000-0003-3960-5720)
- Yifei Gong (ORCID: https://orcid.org/0009-0003-5233-9081)
- Dongzhou Wang (ORCID: https://orcid.org/0000-0001-6216-3604)
- Caixia Guo (ORCID: https://orcid.org/0000-0002-2820-705X)
- Yeran Yang (ORCID: https://orcid.org/0000-0003-2189-2207)
- Tie-Shan Tang (ORCID: https://orcid.org/0000-0001-8975-6338)
- Hui Zheng (ORCID: https://orcid.org/0009-0009-4833-6615)
- Honglin Wu (ORCID: https://orcid.org/0000-0002-1175-5201)
- Hongmei Liu
- W.J. Wu (ORCID: https://orcid.org/0009-0002-7592-9140)
- Xiuxiu Miao
- Hui Fu (ORCID: https://orcid.org/0009-0004-3125-246X)
- Ruiyuan An
Institutions
- Chinese Academy of Sciences (CN)
- Beijing Institute of Genomics (CN)
- Shanghai Center For Bioinformation Technology (CN)
- University of Chinese Academy of Sciences (CN)
- Institute of Zoology (CN)
- Taiyuan University of Technology (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-09
- DOI
- https://doi.org/10.1126/sciadv.adr2643
- Citations
- 7
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- National Natural Science Foundation of China
- State Key Laboratory of Membrane Biology
- Postdoctoral Research Foundation of China