The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export.
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.
Duke Scholars
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Related Subject Headings
- Ubiquitination
- Serine-Arginine Splicing Factors
- RNA, Messenger
- R-Loop Structures
- Neoplasms
- Humans
- Fanconi Anemia Complementation Group Proteins
- Fanconi Anemia Complementation Group D2 Protein
- Fanconi Anemia
- DNA Repair
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Ubiquitination
- Serine-Arginine Splicing Factors
- RNA, Messenger
- R-Loop Structures
- Neoplasms
- Humans
- Fanconi Anemia Complementation Group Proteins
- Fanconi Anemia Complementation Group D2 Protein
- Fanconi Anemia
- DNA Repair