ATM and 53BP1 regulate alternative end joining-mediated V(D)J recombination.

Sci Adv

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Published: August 2024

AI Article Synopsis

  • - G-G phase alternative end joining (A-EJ) is a new DNA repair pathway that leads to specific types of mutations and is distinct from the more common microhomology-mediated end joining (MMEJ), especially during cell division.
  • - The study investigates the roles of various DNA damage response (DDR) genes and factors in supporting A-EJ, particularly during the repair of RAG1/2-initiated double-strand breaks at the Igκ locus.
  • - Key components of A-EJ were identified, like the Parp1-XRCC1/LigIII axis and 53BP1, which are influenced by different DDR activities; this enhances our understanding of DNA repair mechanisms involving the 53BP

Article Abstract

G-G phase alternative end joining (A-EJ) is a recently defined mutagenic pathway characterized by resected deletion and translocation joints that are predominantly direct and are distinguished from A-EJ in cycling cells that rely much more on microhomology-mediated end joining (MMEJ). Using chemical and genetic approaches, we systematically evaluate potential A-EJ factors and DNA damage response (DDR) genes to support this mechanism by mapping the repair fates of RAG1/2-initiated double-strand breaks in the context of Igκ locus V-J recombination and chromosome translocation. Our findings highlight a polymerase theta-independent Parp1-XRCC1/LigIII axis as central A-EJ components, supported by 53BP1 in the context of an Ataxia-telangiectasia mutated (ATM)-activated DDR. Mechanistically, we demonstrate varied changes in short-range resection, MMEJ, and translocation, imposed by compromising specific DDR activities, which include polymerase alpha, Ataxia-telangiectasia and Rad3-related (ATR), DNA2, and Mre11. This study advances our understanding of DNA damage repair within the 53BP1 regulatory domain and the RAG1/2 postcleavage complex.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290492PMC
http://dx.doi.org/10.1126/sciadv.adn4682DOI Listing

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