Genome Stability Unit, St. Vincent's Institute of Medical Research, Fitzroy, Australia.
Department of Medicine, (St Vincent's) University of Melbourne, Fitzroy, Australia.
Nucleus. 2019 Dec;10(1):221-230. doi: 10.1080/19491034.2019.1685246.
Break-induced replication is a specific type of DNA repair that has a co-opted role in telomere extension by telomerase-negative cancer cells. This Alternative Lengthening of Telomeres (or 'ALT') is required for viability in approximately 10% of all carcinomas, but up to 50% of the soft-tissue derived sarcomas. In several recent studies, we and others demonstrate that expression and activity of FANCM, a DNA translocase protein, is essential for the viability of ALT-associated cancers. Here we provide a summary of how and why FANCM depletion leads to deletion of ALT-controlled cancers, predominantly through a hyper-activation of break-induced replication. We also discuss how FANCM can and has been targeted in cancer cell killing, including potential opportunities in ALT and other genetic backgrounds.
断裂诱导复制是一种特定类型的 DNA 修复，它在端粒酶阴性癌细胞中端粒延伸中具有被篡夺的作用。这种端粒的替代性延长（或“ALT”）对于大约 10%的所有癌，但高达 50%的软组织衍生的肉瘤的存活是必需的。在最近的几项研究中，我们和其他人证明，DNA 转位酶蛋白 FANCM 的表达和活性对于 ALT 相关癌症的存活是必不可少的。在这里，我们提供了一个概述，说明为什么和如何 FANCM 耗竭会导致 ALT 控制的癌症的缺失，主要是通过对断裂诱导复制的过度激活。我们还讨论了 FANCM 如何以及已经在癌细胞杀伤中被靶向，包括在 ALT 和其他遗传背景中的潜在机会。
