PDF(Pubmed)
Abstract：
Telomeres protect chromosome ends from unscheduled DNA repair, including from the MRN (MRE11, RAD50, NBS1) complex, which processes double-stranded DNA breaks (DSBs) via activation of the ATM kinase, promotes DNA end-tethering aiding the non-homologous end-joining (NHEJ) pathway, and initiates DSB resection through the MRE11 nuclease. A protein motif (MIN, for MRN inhibitor) inhibits MRN at budding yeast telomeres by binding to RAD50 and evolved at least twice, in unrelated telomeric proteins Rif2 and Taz1. We identify the iDDR motif of human shelterin protein TRF2 as a third example of convergent evolution for this telomeric mechanism for binding MRN, despite the iDDR lacking sequence homology to the MIN motif. CtIP is required for activation of MRE11 nuclease action, and we provide evidence for binding of a short C-terminal region of CtIP to a RAD50 interface that partly overlaps with the iDDR binding site, indicating that the interaction is mutually exclusive. In addition, we show that the iDDR impairs the DNA binding activity of RAD50. These results highlight direct inhibition of MRN action as a crucial role of telomeric proteins across organisms and point to multiple mechanisms enforced by the iDDR to disable the many activities of the MRN complex.
摘要：
端粒保护染色体末端免受计划外的DNA修复，包括来自MRN（MRE11，RAD50，NBS1）复合物，通过激活ATM激酶处理双链DNA断裂（DSB），促进DNA末端连接，帮助非同源末端连接（NHEJ）途径，并通过MRE11核酸酶启动DSB切除。蛋白质基序（MIN，对于MRN抑制剂）通过与RAD50结合而抑制出芽酵母端粒的MRN，并进化至少两次，不相关的端粒蛋白Rif2和Taz1。我们确定了人类shelterin蛋白TRF2的iDDR基序，作为这种结合MRN的端粒机制的趋同进化的第三个例子，尽管iDDR缺乏与MIN基序的序列同源性。CtIP是激活MRE11核酸酶作用所必需的，我们提供了CtIP的短C端区域与RAD50界面结合的证据，该界面与iDDR结合位点部分重叠，表明这种互动是相互排斥的。此外,我们显示iDDR损害RAD50的DNA结合活性。这些结果突出了MRN作用的直接抑制是端粒蛋白在生物体中的关键作用，并指出了iDDR强制实施的多种机制以禁用MRN复合物的许多活性。
