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

doi:10.1016/j.celrep.2023.113610

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

Cell Rep. 2024 Jan 23;43(1):113610. doi: 10.1016/j.celrep.2023.113610. Epub 2024 Jan 1.

Authors

Anne Olazabal-Herrero¹, Boxue He², Youngho Kwon³, Abhishek K Gupta⁴, Arijit Dutta³, Yuxin Huang³, Prajwal Boddu⁴, Zhuobin Liang⁵, Fengshan Liang¹, Yaqun Teng⁶, Li Lan⁶, Xiaoyong Chen⁷, Huadong Pei⁸, Manoj M Pillai⁴, Patrick Sung⁹, Gary M Kupfer¹⁰

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Section of Hematology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, CT 06511, USA.
⁵ Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
⁶ 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.
⁷ Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA.
⁸ Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
⁹ 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. Electronic address: [email protected].
¹⁰ Department of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA. Electronic address: [email protected].

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.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Active Transport, Cell Nucleus
DNA Damage
DNA Repair
Fanconi Anemia Complementation Group D2 Protein / genetics
Fanconi Anemia Complementation Group D2 Protein / metabolism
Fanconi Anemia Complementation Group Proteins / metabolism
Fanconi Anemia* / metabolism
Humans
Neoplasms*
R-Loop Structures
RNA, Messenger / genetics
RNA, Messenger / metabolism
Serine-Arginine Splicing Factors / genetics
Serine-Arginine Splicing Factors / metabolism
Ubiquitination

Substances

Fanconi Anemia Complementation Group Proteins
Fanconi Anemia Complementation Group D2 Protein
RNA, Messenger
FANCD2 protein, human
FANCI protein, human
SRSF1 protein, human
Serine-Arginine Splicing Factors

Supplementary concepts

Fanconi Anemia, Complementation Group I

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding