8SH0

Structure of human POT1 DNA binding domain bound to a 5'-phosphorylated junction of a telomeric DNA hairpin with a 3'-overhang

Summary for 8SH0

• Entry DOI: 10.2210/pdb8sh0/pdb
• Descriptor: Protection of telomeres protein 1, DNA (5'-D(P*CP*CP*AP*GP*CP*AP*GP*GP*GP*GP*TP*TP*AP*GP*GP*GP*TP*TP*AP*G)-3'), ACETATE ION, ... (4 entities in total)
• Functional Keywords: shelterin, telomere, dna junction, 5'-phosphorylated, pot-hole, chromosome end protection, pot1, dbd, pot1-dna complex, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 40244.00

Authors

Nandakumar, J.,Tesmer, V.M. (deposition date: 2023-04-13, release date: 2023-08-30)

Primary citation

Tesmer, V.M.,Brenner, K.A.,Nandakumar, J.
Human POT1 protects the telomeric ds-ss DNA junction by capping the 5' end of the chromosome.
Science, 381:771-778, 2023

PubMed 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.

PubMed: 37590346
DOI: 10.1126/science.adi2436

Experimental method

X-RAY DIFFRACTION (2.16 Å)