8RD4

Telomeric RAP1:DNA-PK complex

Summary for 8RD4

• Entry DOI: 10.2210/pdb8rd4/pdb
• EMDB information: 19065
• Descriptor: DNA-dependent protein kinase catalytic subunit, Telomeric repeat-binding factor 2-interacting protein 1, X-ray repair cross-complementing protein 6, ... (6 entities in total)
• Functional Keywords: telomere nhej brct domain sap domain, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 728439.08

Authors

Eickhoff, P.,Fisher, C.E.L.,Inian, O.,Guettler, S.,Douglas, M.E. (deposition date: 2023-12-07, release date: 2025-03-05, Last modification date: 2025-07-16)

Primary citation

Eickhoff, P.,Sonmez, C.,Fisher, C.E.L.,Inian, O.,Roumeliotis, T.I.,Dello Stritto, A.,Mansfeld, J.,Choudhary, J.S.,Guettler, S.,Lottersberger, F.,Douglas, M.E.
Chromosome end protection by RAP1-mediated inhibition of DNA-PK.
Nature, 642:1090-1096, 2025

PubMed Abstract: During classical non-homologous end joining (cNHEJ), DNA-dependent protein kinase (DNA-PK) encapsulates free DNA ends, forming a recruitment platform for downstream end-joining factors including ligase 4 (LIG4). DNA-PK can also bind telomeres and regulate their resection, but does not initiate cNHEJ at this position. How the end-joining process is regulated in this context-specific manner is currently unclear. Here we show that the shelterin components TRF2 and RAP1 form a complex with DNA-PK that directly represses its end-joining function at telomeres. Biochemical experiments and cryo-electron microscopy reveal that when bound to TRF2, RAP1 establishes a network of interactions with KU and DNA that prevents DNA-PK from recruiting LIG4. In mouse and human cells, RAP1 is redundant with the Apollo nuclease in repressing cNHEJ at chromosome ends, demonstrating that the inhibition of DNA-PK prevents telomere fusions in parallel with overhang-dependent mechanisms. Our experiments show that the end-joining function of DNA-PK is directly and specifically repressed at telomeres, establishing a molecular mechanism for how individual linear chromosomes are maintained in mammalian cells.

PubMed: 40240611
DOI: 10.1038/s41586-025-08896-1

Experimental method

ELECTRON MICROSCOPY (3.58 Å)