PDF(Pubmed)
Abstract：
DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of these pathways is dependent on the local chromatin context, but the underlying mechanisms are poorly understood. By combining knockout screening with a dual MMEJ:NHEJ reporter inserted in 19 different chromatin environments, we identified dozens of DNA repair proteins that modulate pathway balance dependent on the local chromatin state. Proteins that favor NHEJ mostly synergize with euchromatin, while proteins that favor MMEJ generally synergize with distinct types of heterochromatin. Examples of the former are BRCA2 and POLL, and of the latter the FANC complex and ATM. Moreover, in a diversity of human cancer types, loss of several of these proteins alters the distribution of pathway-specific mutations between heterochromatin and euchromatin. Together, these results uncover a complex network of proteins that regulate MMEJ:NHEJ balance in a chromatin context-dependent manner.
摘要：
DNA双链断裂通过多种途径修复，包括非同源末端连接(NHEJ)和微同源介导的末端连接(MMEJ)。这些途径的平衡取决于局部染色质环境，但潜在的机制却知之甚少。通过将敲除筛选与插入19种不同染色质环境中的双重MMEJ：NHEJ报道分子相结合，我们鉴定了几十种DNA修复蛋白,这些蛋白调节依赖于局部染色质状态的通路平衡.有利于NHEJ的蛋白质大多与常染色质协同作用，而有利于MMEJ的蛋白质通常与不同类型的异染色质协同作用。前者的例子是BRCA2和POLL，后者是FANC综合体和ATM。此外，在不同的人类癌症类型中，其中几种蛋白质的丢失改变了异染色质和常染色质之间通路特异性突变的分布。一起,这些结果揭示了一个复杂的蛋白质网络,这些蛋白质以染色质上下文依赖的方式调节MMEJ:NHEJ平衡.
