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

• Published in: Cell reports (Cambridge) 2024-01, Vol.43 (1), p.113610-113610, Article 113610
• Main Authors: Olazabal-Herrero, Anne, He, Boxue, Kwon, Youngho, Gupta, Abhishek K., Dutta, Arijit, Huang, Yuxin, Boddu, Prajwal, Liang, Zhuobin, Liang, Fengshan, Teng, Yaqun, Lan, Li, Chen, Xiaoyong, Pei, Huadong, Pillai, Manoj M., Sung, Patrick, Kupfer, Gary M.
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; CP: Molecular biology; DNA Damage; DNA Repair; FANCD2; Fanconi Anemia - metabolism; Fanconi Anemia Complementation Group D2 Protein - genetics; Fanconi Anemia Complementation Group D2 Protein - metabolism; Fanconi Anemia Complementation Group Proteins - metabolism; Humans; monoubiquitination; mRNA export; Neoplasms; NXF1; R-Loop Structures; R-loops; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; SRSF1; Ubiquitination
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113610

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. [Display omitted] •SRSF1 activates the FA pathway by binding and stimulating FANCD2 ubiquitination•FANCD2 ubiquitination is crucial for the formation of NXF1-SRSF1 export complex•FANCD2 monoubiquitination is critical for NXF1-mediated mRNA export•SRSF1 cancer mutants fail to bind FANCD2 and NXF1, leading to inefficient mRNA export While the Fanconi anemia pathway has a well-characterized function in DNA crosslink repair, its newly uncovered role in regulating R-loop metabolism has not been fully understood. Olazabal-Herrero et al. reveal that FANCD2 functions in NXF1-SRSF1-mediated mRNA export regulation, preventing R-loop formation and subsequent genomic instability.