Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.
Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.
复制标题
减数分裂蛋白 SYCP2 通过 R 环介导的 DNA 修复赋予对 DNA 损伤剂的抵抗力。
DOI：
10.1038/s41467-024-45693-2
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发表时间：
2024
影响因子：
16.6
通讯作者：
Rueda,Bo
中科院分区：
文献类型：
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作者：
Wang,Yumin;Gao,Boya;Zhang,Luyuan;Wang,Xudong;Zhu,Xiaolan;Yang,Haibo;Zhang,Fengqi;Zhu,Xueping;Zhou,Badi;Yao,Sean;Nagayama,Aiko;Lee,Sanghoon;Ouyang,Jian;Koh,Siang-Boon;Eisenhauer,EricL;Zarrella,Dominique;Lu,Kate;Rueda,Bo
靶向DNA损伤反应（DDR）的药物广泛用于癌症治疗，但对这些药物的耐药性仍然是一个主要的临床挑战。在这里，我们发现SYCP 2，联会复合体中的减数分裂蛋白，在乳腺癌和卵巢癌中异常且普遍表达，并与对DDR药物的广泛耐药性相关。SYCP 2通过转录偶联同源重组（TC-HR）增强DNA双链断裂（DSB）的修复。SYCP 2促进DSB处的R环形成，并独立于BRCA 1促进RAD 51募集。SYCP 2缺失损害RAD 51定位，降低TC-HR，并使肿瘤对PARP和拓扑异构酶I（TOP 1）抑制剂敏感。此外，我们对两个临床队列的研究发现，SYCP 2过表达与乳腺癌对抗体偶联的TOP1抑制剂的耐药性和卵巢癌对铂类治疗的耐药性相关。总的来说，我们的数据表明SYCP 2通过刺激R环介导的DSB修复赋予癌细胞对DNA损伤剂的抗性，从而提供改善DDR治疗的机会。
Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed in breast and ovarian cancers and associated with broad resistance to DDR drugs. Mechanistically, SYCP2 enhances the repair of DNA double-strand breaks (DSBs) through transcription-coupled homologous recombination (TC-HR). SYCP2 promotes R-loop formation at DSBs and facilitates RAD51 recruitment independently of BRCA1. SYCP2 loss impairs RAD51 localization, reduces TC-HR, and renders tumors sensitive to PARP and topoisomerase I (TOP1) inhibitors. Furthermore, our studies of two clinical cohorts find that SYCP2 overexpression correlates with breast cancer resistance to antibody-conjugated TOP1 inhibitor and ovarian cancer resistance to platinum treatment. Collectively, our data suggest that SYCP2 confers cancer cell resistance to DNA-damaging agents by stimulating R-loop-mediated DSB repair, offering opportunities to improve DDR therapy.