Cell Reports: The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export (Sung & Lab)

Published On: January 17, 2024
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Highlights

  • RSF1 activates the FA pathway by binding and stimulating FANCD2 ubiquitination
  • ANCD2 ubiquitination is crucial for the formation of NXF1-SRSF1 export complex
  • ANCD2 monoubiquitination is critical for NXF1-mediated mRNA export
  • RSF1 cancer mutants fail to bind FANCD2 and NXF1, leading to inefficient mRNA export

Summary

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.

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Article Categories: Research Paper

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