新たな発見が染色体末端の保護機構を解明(New discovery reveals how chromosome ends can be protected)

2025-09-09 リンショーピング大学

If two chromosomes are fused, as seen here, the consequences can be catastrophic for the cell and the organism.Photographer:Thor Balkhed

<関連情報>

• https://liu.se/en/news-item/new-discovery-reveals-how-chromosome-ends-can-be-protected
• https://www.nature.com/articles/s41586-025-08896-1

RAP1によるDNA-PK阻害を介した染色体末端の保護 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 & Max E. Douglas
Nature  Published:16 April 2025
DO:Ihttps://doi.org/10.1038/s41586-025-08896-1

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 resection^2,3,4, 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.