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
Affiliations
Anne Olazabal-Herrero
Department of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA; Section of Hematology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, CT 06511, USA
Boxue He
Department of Biochemistry and Structural Biology, Greehey Children’s Cancer Research Institute, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha 410011, China
Youngho Kwon
Department of Biochemistry and Structural Biology, Greehey Children’s Cancer Research Institute, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Abhishek K. Gupta
Section of Hematology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, CT 06511, USA
Arijit Dutta
Department of Biochemistry and Structural Biology, Greehey Children’s Cancer Research Institute, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Yuxin Huang
Department of Biochemistry and Structural Biology, Greehey Children’s Cancer Research Institute, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Prajwal Boddu
Section of Hematology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, CT 06511, USA
Zhuobin Liang
Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen 518132, China
Fengshan Liang
Department of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA; Section of Hematology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, CT 06511, USA
Yaqun Teng
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
Li Lan
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
Xiaoyong Chen
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA
Huadong Pei
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
Manoj M. Pillai
Section of Hematology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, CT 06511, USA
Patrick Sung
Department of Biochemistry and Structural Biology, Greehey Children’s Cancer Research Institute, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Corresponding author
Gary M. Kupfer
Department of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA; Corresponding author
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.
