CTC1-STN1-TEN1 controls DNA break repair pathway choice via DNA end resection blockade

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-05-22 DOI:10.1126/science.adt3034

Cody M. Rogers, Hardeep Kaur, Michelle L. Swift, Vivek B. Raina, Shuo Zhou, Ajinkya S. Kawale, Shahrez Syed, Korilynn G. Kelly, Angela M. Jasper, Sameer Salunkhe, Youngho Kwon, Jeffrey Wang, Aida Badamchi Shabestari, James M. Daley, Adam Sacks, Maria E. Gaczynska, Pawel A. Osmulski, Yashpal Rawal, Nozomi Tomimatsu, Simon A. Gayther, Kate Lawrenson, Sandeep Burma, Elizabeth V. Wasmuth, Shaun K. Olsen, Weixing Zhao, Robert Hromas, David S. Libich, Alexander V. Mazin, Daohong Zhou, Eric C. Greene, Dipanjan Chowdhury, Patrick Sung

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引用次数: 0

Abstract

Antagonistic activities of the 53BP1 axis and the tumor suppressor BRCA1-BARD1 determine whether DNA double-strand breaks (DSBs) are repaired by end joining or homologous recombination. We show that the CTC1-STN1-TEN1 (CST) complex, a central 53BP1 axis component, suppresses DNA end resection by EXO1 and the BLM-DNA2 helicase-nuclease complex but acts by distinct mechanisms in restricting these entities. Whereas BRCA1-BARD1 alleviates the CST-imposed EXO1 blockade, it has little effect on BLM-DNA2 restriction. CST mutants impaired for DNA binding or BLM–EXO1 interaction exhibit a hyper-resection phenotype and render BRCA1-deficient cells resistant to poly(ADP–ribose) polymerase (PARP) inhibitors. Our findings mechanistically define the crucial role of CST in DNA DSB repair pathway choice and have implications for understanding cancer therapy resistance stemming from dysfunction of the 53BP1 axis.

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CTC1-STN1-TEN1通过DNA末端切除阻断控制DNA断裂修复途径的选择

53BP1轴和肿瘤抑制因子BRCA1-BARD1的拮抗活性决定了DNA双链断裂（DSBs）是否通过末端连接或同源重组修复。我们发现CTC1-STN1-TEN1 （CST）复合体，53BP1轴的中心成分，抑制EXO1和BLM-DNA2解旋酶-核酸酶复合体的DNA末端切除，但通过不同的机制限制这些实体。尽管BRCA1-BARD1减轻了cst施加的EXO1阻断，但它对BLM-DNA2限制的影响很小。DNA结合或BLM-EXO1相互作用受损的CST突变体表现出超切除表型，并使brca1缺陷细胞对聚（adp -核糖）聚合酶（PARP）抑制剂产生抗性。我们的研究结果从机制上定义了CST在DNA DSB修复途径选择中的关键作用，并对理解由53BP1轴功能障碍引起的癌症治疗耐药具有重要意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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