Department of Genetics, MD Anderson Cancer Center, Houston, TX, USA.
EMBO J. 2010 Aug 4;29(15):2598-610. doi: 10.1038/emboj.2010.142. Epub 2010 Jun 29.
Repair of DNA double-stranded breaks (DSBs) is crucial for the maintenance of genome stability. DSBs are repaired by either error prone non-homologous end-joining (NHEJ) or error-free homologous recombination. NHEJ precedes either by a classic, Lig4-dependent process (C-NHEJ) or an alternative, Lig4-independent one (A-NHEJ). Dysfunctional telomeres arising either through natural attrition due to telomerase deficiency or by removal of telomere-binding proteins are recognized as DSBs. In this report, we studied which end-joining pathways are required to join dysfunctional telomeres. In agreement with earlier studies, depletion of Trf2 resulted in end-to-end chromosome fusions mediated by the C-NHEJ pathway. In contrast, removal of Tpp1-Pot1a/b initiated robust chromosome fusions that are mediated by A-NHEJ. C-NHEJ is also dispensable for the fusion of naturally shortened telomeres. Our results reveal that telomeres engage distinct DNA repair pathways depending on how they are rendered dysfunctional, and that A-NHEJ is a major pathway to process dysfunctional telomeres.
修复 DNA 双链断裂 (DSB) 对于维持基因组稳定性至关重要。DSB 可以通过易错的非同源末端连接 (NHEJ) 或无差错的同源重组来修复。NHEJ 可以通过经典的、依赖 Lig4 的过程 (C-NHEJ) 或替代的、不依赖 Lig4 的过程 (A-NHEJ) 先发生。由于端粒酶缺乏或端粒结合蛋白去除而自然损耗导致的功能失调的端粒被视为 DSB。在本报告中，我们研究了哪些末端连接途径是连接功能失调的端粒所必需的。与早期的研究一致，Trf2 的耗竭导致了由 C-NHEJ 途径介导的端到端染色体融合。相比之下，Tpp1-Pot1a/b 的去除引发了由 A-NHEJ 介导的强烈的染色体融合。C-NHEJ 对于自然缩短的端粒的融合也是可有可无的。我们的结果表明，端粒根据其功能失调的方式，参与不同的 DNA 修复途径，并且 A-NHEJ 是处理功能失调的端粒的主要途径。
