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SPIN1 通过促进 Tip60 与 H3K9me3 的结合来促进化学抗性和 HR 修复。

SPIN1 facilitates chemoresistance and HR repair by promoting Tip60 binding to H3K9me3.

机构信息

College of Life Sciences, Hebei University, Baoding, Hebei Province, 071002, China.

出版信息

EMBO Rep. 2024 Sep;25(9):3970-3989. doi: 10.1038/s44319-024-00219-1. Epub 2024 Aug 1.

DOI:10.1038/s44319-024-00219-1
PMID:39090319
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11387427/
Abstract

The tandem Tudor-like domain-containing protein Spindlin1 (SPIN1) is a transcriptional coactivator with critical functions in embryonic development and emerging roles in cancer. However, the involvement of SPIN1 in DNA damage repair has remained unclear. Our study shows that SPIN1 is recruited to DNA lesions through its N-terminal disordered region that binds to Poly-ADP-ribose (PAR), and facilitates homologous recombination (HR)-mediated DNA damage repair. SPIN1 promotes H3K9me3 accumulation at DNA damage sites and enhances the interaction between H3K9me3 and Tip60, thereby promoting the activation of ATM and HR repair. We also show that SPIN1 increases chemoresistance. These findings reveal a novel role for SPIN1 in the activation of H3K9me3-dependent DNA repair pathways, and suggest that SPIN1 may contribute to cancer chemoresistance by modulating the efficiency of double-strand break (DSB) repair.

摘要

串联 Tudor 样结构域蛋白 Spindlin1（SPIN1）是一种转录共激活因子，在胚胎发育中具有关键作用，并在癌症中发挥新的作用。然而，SPIN1 参与 DNA 损伤修复的情况尚不清楚。我们的研究表明，SPIN1 通过其与聚 ADP-核糖（PAR）结合的 N 端无规卷曲结构域被招募到 DNA 损伤部位，并促进同源重组（HR）介导的 DNA 损伤修复。SPIN1 促进 H3K9me3 在 DNA 损伤部位的积累，并增强 H3K9me3 与 Tip60 之间的相互作用，从而促进 ATM 和 HR 修复的激活。我们还表明，SPIN1 增加了化疗耐药性。这些发现揭示了 SPIN1 在激活依赖 H3K9me3 的 DNA 修复途径中的新作用，并表明 SPIN1 可能通过调节双链断裂（DSB）修复的效率来促进癌症的化疗耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f34/11387427/677524992e64/44319_2024_219_Fig10_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f34/11387427/888ad0a98334/44319_2024_219_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f34/11387427/4a0f892a6de6/44319_2024_219_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f34/11387427/d2117adb14ff/44319_2024_219_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f34/11387427/677524992e64/44319_2024_219_Fig10_ESM.jpg

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