Abraxas suppresses DNA end resection and limits break-induced replication by controlling SLX4/MUS81 chromatin loading in response to TOP1 inhibitor-induced DNA damage

Nat Commun. 2021 Jul 16;12(1):4373. doi: 10.1038/s41467-021-24665-w.

Abstract

Although homologous recombination (HR) is indicated as a high-fidelity repair mechanism, break-induced replication (BIR), a subtype of HR, is a mutagenic mechanism that leads to chromosome rearrangements. It remains poorly understood how cells suppress mutagenic BIR. Trapping of Topoisomerase 1 by camptothecin (CPT) in a cleavage complex on the DNA can be transformed into single-ended double-strand breaks (seDSBs) upon DNA replication or colliding with transcriptional machinery. Here, we demonstrate a role of Abraxas in limiting seDSBs undergoing BIR-dependent mitotic DNA synthesis. Through counteracting K63-linked ubiquitin modification, Abraxas restricts SLX4/Mus81 recruitment to CPT damage sites for cleavage and subsequent resection processed by MRE11 endonuclease, CtIP, and DNA2/BLM. Uncontrolled SLX4/MUS81 loading and excessive end resection due to Abraxas-deficiency leads to increased mitotic DNA synthesis via RAD52- and POLD3- dependent, RAD51-independent BIR and extensive chromosome aberrations. Our work implicates Abraxas/BRCA1-A complex as a critical regulator that restrains BIR for protection of genome stability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Camptothecin / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Chromatin / genetics
  • Chromatin / metabolism*
  • DNA Breaks, Double-Stranded
  • DNA Damage / drug effects*
  • DNA Damage / genetics
  • DNA Polymerase III / metabolism
  • DNA Replication / genetics
  • DNA Topoisomerases, Type I / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endonucleases / genetics
  • Endonucleases / metabolism*
  • Homologous Recombination
  • Humans
  • MRE11 Homologue Protein / metabolism
  • Mice
  • RNA, Small Interfering
  • Rad52 DNA Repair and Recombination Protein / genetics
  • Rad52 DNA Repair and Recombination Protein / metabolism
  • Recombinases / genetics
  • Recombinases / metabolism*
  • Topoisomerase I Inhibitors / pharmacology
  • Ubiquitination

Substances

  • ABRAXAS1 protein, human
  • Carrier Proteins
  • Chromatin
  • DNA-Binding Proteins
  • MRE11 protein, human
  • RAD52 protein, human
  • RNA, Small Interfering
  • Rad52 DNA Repair and Recombination Protein
  • Recombinases
  • Topoisomerase I Inhibitors
  • POLD3 protein, human
  • DNA Polymerase III
  • Endonucleases
  • MRE11 Homologue Protein
  • MUS81 protein, human
  • SLX4 protein, human
  • DNA Topoisomerases, Type I
  • TOP1 protein, human
  • Camptothecin