The splicing factor XAB2 interacts with ERCC1-XPF and XPG for R-loop processing

Nat Commun. 2021 May 26;12(1):3153. doi: 10.1038/s41467-021-23505-1.


RNA splicing, transcription and the DNA damage response are intriguingly linked in mammals but the underlying mechanisms remain poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the splicing factor XAB2 interacts with the core spliceosome and that it binds to spliceosomal U4 and U6 snRNAs and pre-mRNAs in developing livers. XAB2 depletion leads to aberrant intron retention, R-loop formation and DNA damage in cells. Studies in illudin S-treated cells and Csbm/m developing livers reveal that transcription-blocking DNA lesions trigger the release of XAB2 from all RNA targets tested. Immunoprecipitation studies reveal that XAB2 interacts with ERCC1-XPF and XPG endonucleases outside nucleotide excision repair and that the trimeric protein complex binds RNA:DNA hybrids under conditions that favor the formation of R-loops. Thus, XAB2 functionally links the spliceosomal response to DNA damage with R-loop processing with important ramifications for transcription-coupled DNA repair disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA Damage / drug effects
  • DNA Repair*
  • DNA-Binding Proteins / metabolism*
  • Endonucleases / metabolism*
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Knock-In Techniques
  • Gene Knockdown Techniques
  • Liver / growth & development
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Mouse Embryonic Stem Cells
  • Nuclear Proteins / metabolism*
  • Polycyclic Sesquiterpenes / pharmacology
  • R-Loop Structures / genetics
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA Splicing Factors / genetics
  • RNA Splicing Factors / metabolism*
  • RNA, Small Nuclear
  • RNA-Seq
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Spliceosomes / metabolism
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • DNA excision repair protein ERCC-5
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Polycyclic Sesquiterpenes
  • RNA Precursors
  • RNA Splicing Factors
  • RNA, Small Nuclear
  • Recombinant Proteins
  • Transcription Factors
  • U4 small nuclear RNA
  • U6 small nuclear RNA
  • XAB2 protein, mouse
  • xeroderma pigmentosum group F protein
  • Endonucleases
  • Ercc1 protein, mouse
  • illudin S