Chromosome end protection by RAP1-mediated inhibition of DNA-PK

Patrik Eickhoff, Ceylan Sonmez, Charlotte E. L. Fisher, Oviya Inian, Theodoros I. Roumeliotis, Angela dello Stritto, Jörg Mansfeld, Jyoti S. Choudhary, Sebastian Guettler, Francisca Lottersberger () and Max E. Douglas ()
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Patrik Eickhoff: The Institute of Cancer Research
Ceylan Sonmez: Linköping University
Charlotte E. L. Fisher: The Institute of Cancer Research
Oviya Inian: The Institute of Cancer Research
Theodoros I. Roumeliotis: The Institute of Cancer Research
Angela dello Stritto: Linköping University
Jörg Mansfeld: The Institute of Cancer Research
Jyoti S. Choudhary: The Institute of Cancer Research
Sebastian Guettler: The Institute of Cancer Research
Francisca Lottersberger: Linköping University
Max E. Douglas: The Institute of Cancer Research

Nature, 2025, vol. 642, issue 8069, 1090-1096

Abstract: 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)1. DNA-PK can also bind telomeres and regulate their resection2–4, 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.

Date: 2025
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DOI: 10.1038/s41586-025-08896-1

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