SNAP output for PDB entry 8sh1 [SNAP web server]

PDB-id

8sh1; SNAP-derived features in text and JSON formats; DNAproDB

Class

DNA binding protein-DNA

Method

X-ray (2.6 Å)

Summary

Structure of human pot1 DNA binding domain bound to a 5'-phosphorylated junction of a telomeric double-stranded DNA duplex with a 3'-overhang

Reference

Tesmer VM, Brenner KA, Nandakumar J (2023): "Human POT1 protects the telomeric ds-ss DNA junction by capping the 5' end of the chromosome." Science, 381, 771-778. doi: 10.1126/science.adi2436.

Abstract

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.