Senataxin and DNA-PKcs redundantly promote non-homologous end joining repair of DNA double strand breaks during V(D)J recombination. Academic Article uri icon

Overview

abstract

  • Nonhomologous end joining (NHEJ) is required for repairing DNA double strand breaks (DSBs) generated by the RAG endonuclease during lymphocyte antigen receptor gene assembly by V(D)J recombination. The ataxia telangiectasia-mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) kinases regulate functionally redundant pathways required for NHEJ. Here, we report that loss of the senataxin helicase leads to a strong defect in RAG DSB repair upon inactivation of DNA-PKcs. The NHEJ function of senataxin is redundant with the RECQL5 helicase and the HLTF translocase and is epistatic with ATM. Co-inactivation of ATM, RECQL5, and HLTF results in an NHEJ defect similar to that from the combined deficiency of DNA-PKcs and senataxin or losing senataxin, RECQL5, and HLTF. These data suggest that ATM and DNA-PKcs regulate the functions of senataxin and RECQL5/HLTF, respectively, to provide redundant support for NHEJ.

publication date

  • June 20, 2025

Research

keywords

  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair
  • DNA Helicases
  • DNA-Activated Protein Kinase
  • V(D)J Recombination

Identity

PubMed Central ID

  • PMC12180482

Digital Object Identifier (DOI)

  • 10.1126/sciadv.ads5272

PubMed ID

  • 40540553

Additional Document Info

volume

  • 11

issue

  • 25