WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer.
WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer.
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DOI：
10.1002/bies.202200057
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发表时间：
2022-08
期刊：
影响因子：
4
通讯作者：
Brosh, Robert M., Jr.
中科院分区：
文献类型：
--
作者：
Datta, Arindam;Brosh, Robert M., Jr.
关键词：
遗传性乳腺癌和卵巢癌通常归因于肿瘤抑制基因 BRCA1 和 BRCA2 的种系突变。 BRCA1/2 可修复双链断裂并抑制不稳定复制叉的死亡。我们的工作阐明了早衰症维尔纳综合征中 BRCA2 与 WRN DNA 解旋酶/核酸外切酶缺陷之间的动态相互作用。 WRN 和 BRCA2 参与互补途径来稳定癌细胞中的复制叉，从而使它们能够增殖。 WRN 和 BRCA2 的功能重叠是否与新合成 DNA 片段之间间隙的复制、端粒保护和/或二级 DNA 结构的代谢相关仍有待确定。对复制应激期间引发机制的理解取得的进展促使业界重新考虑癌症治疗的途径。 PARP 或拓扑异构酶抑制剂的研究成果为研究 WRN 的作用机制提供了工作模型。我们讨论这些主题，重点关注复制应激条件下 WRN-BRCA2 遗传相互作用的影响。抑制 WRN 解旋酶重塑 BRCA2 缺陷癌细胞中停滞的 DNA 复制叉的作用会导致基因组不稳定和癌细胞死亡。使用 BioRender.com 创建。
Hereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double-strand breaks and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the WRN DNA helicase/exonuclease defective in the premature aging disorder Werner syndrome. WRN and BRCA2 participate in complementary pathways to stabilize replication forks in cancer cells, allowing them to proliferate. Whether the functional overlap of WRN and BRCA2 is relevant to replication at gaps between newly synthesized DNA fragments, protection of telomeres, and/or metabolism of secondary DNA structures remains to be determined. Advances in understanding the mechanisms elicited during replication stress have prompted the community to reconsider avenues for cancer therapy. Insights from studies of PARP or topoisomerase inhibitors provide working models for the investigation of WRN’s mechanism of action. We discuss these topics, focusing on the implications of the WRN-BRCA2 genetic interaction under conditions of replication stress. Suppression of WRN helicase’s action to remodel stalled DNA replication forks in BRCA2-deficient cancer cells causes genomic instability and cancer cell killing. Created with BioRender.com.
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