Massachusetts General Hospital Cancer Center, Harvard Medical School, 13th Street, Charlestown, MA, 02129, USA.
Department of Molecular Biology and Microbiology, Duke University School of Medicine, 213 Research Drive, Durham, NC, 27710, USA.
Nat Commun. 2024 Feb 21;15(1):1568. doi: 10.1038/s41467-024-45693-2.
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.
靶向 DNA 损伤反应 (DDR) 的药物被广泛应用于癌症治疗，但这些药物的耐药性仍然是一个主要的临床挑战。在这里，我们表明，联会复合体中的减数分裂蛋白 SYCP2 在乳腺癌和卵巢癌中异常且普遍表达，并与广泛的 DDR 药物耐药性相关。从机制上讲，SYCP2 通过转录偶联同源重组（TC-HR）增强 DNA 双链断裂（DSB）的修复。SYCP2 促进 DSB 处 R 环的形成，并独立于 BRCA1 促进 RAD51 的募集。SYCP2 的缺失会损害 RAD51 的定位，减少 TC-HR，并使肿瘤对 PARP 和拓扑异构酶 I（TOP1）抑制剂敏感。此外，我们对两个临床队列的研究发现，SYCP2 的过表达与乳腺癌对抗体偶联 TOP1 抑制剂的耐药性和卵巢癌对铂类治疗的耐药性相关。总之，我们的数据表明，SYCP2 通过刺激 R 环介导的 DSB 修复赋予癌细胞对 DNA 损伤剂的耐药性，为改善 DDR 治疗提供了机会。
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