The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export

Anne Olazabal-Herrero, Boxue He, Youngho Kwon, Abhishek K. Gupta, Arijit Dutta, Yuxin Huang, Prajwal Boddu, Zhuobin Liang, Fengshan Liang, Yaqun Teng, Li Lan, Xiaoyong Chen, Huadong Pei, Manoj M. Pillai, Patrick Sung, Gary M. Kupfer

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, and cancer susceptibility. The central FA protein complex FANCI/FANCD2 (ID2) is activated by monoubiquitination and recruits DNA repair proteins for interstrand crosslink (ICL) repair and replication fork protection. Defects in the FA pathway lead to R-loop accumulation, which contributes to genomic instability. Here, we report that the splicing factor SRSF1 and FANCD2 interact physically and act together to suppress R-loop formation via mRNA export regulation. We show that SRSF1 stimulates FANCD2 monoubiquitination in an RNA-dependent fashion. In turn, FANCD2 monoubiquitination proves crucial for the assembly of the SRSF1-NXF1 nuclear export complex and mRNA export. Importantly, several SRSF1 cancer-associated mutants fail to interact with FANCD2, leading to inefficient FANCD2 monoubiquitination, decreased mRNA export, and R-loop accumulation. We propose a model wherein SRSF1 and FANCD2 interaction links DNA damage response to the avoidance of pathogenic R-loops via regulation of mRNA export.

Original languageEnglish (US)
Article number113610
JournalCell Reports
Volume43
Issue number1
DOIs
StatePublished - Jan 23 2024
Externally publishedYes

Keywords

  • CP: Molecular biology
  • DNA damage
  • FANCD2
  • NXF1
  • R-loops
  • RNA
  • SRSF1
  • mRNA export
  • monoubiquitination

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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