Human POT1 protects the telomeric ds-ss DNA junction by capping the 5′ end of the chromosome

• 成果类型: Article
• 署名作者: Tesmer, Valerie M.; Brenner, Kirsten A.; Nandakumar, Jayakrishnan
• 署名单位: University of Michigan System; University of Michigan
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-14083
• DOI: 10.1126/science.adi2436
• 发表日期: 2023-08-18
• 页码: 771-778
• 关键词: binding-protein; crystal-structure; strand; tpp1; atr; complex; domain; RECOGNITION; overhangs; resection

摘要

Protection of telomeres 1 (POT1) is the 3 ' single-stranded overhang-binding telomeric protein that prevents an ataxia telangiectasia and Rad3-related (ATR) DNA damage response (DDR) at chromosome ends. What precludes the DDR machinery from accessing the telomeric double-stranded-single-stranded junction is unknown. We demonstrate that human POT1 binds this junction by recognizing the phosphorylated 5 ' end of the chromosome. High-resolution crystallographic structures reveal that the junction is capped by POT1 through a POT-hole surface, the mutation of which compromises junction protection in vitro and telomeric 5 '-end definition and DDR suppression in human cells. Whereas both mouse POT1 paralogs bind the single-stranded overhang, POT1a, not POT1b, contains a POT-hole and binds the junction, which explains POT1a's sufficiency for end protection. Our study shifts the paradigm for DDR suppression at telomeres by highlighting the importance of protecting the double-stranded-single-stranded junction.