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Nat Commun. 2018 Apr 12;9(1):1418. doi: 10.1038/s41467-018-03817-5.

GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1.

Author information

1
Institut de Recherches Cliniques de Montréal, IRCM, Montréal, QC, H2W 1R7, Canada.
2
Segal Cancer Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
3
Departments of Pathology and Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
4
Department of Hematology, University Hospital, Essen, 45147, Germany.
5
Department of Medicine, Université de Montréal, Montreal, H3T 1J4, QC, Canada.
6
Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, H1T 2M4, QC, Canada.
7
Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montreal, H1T 2M4, QC, Canada.
8
Département de Médecine, Université de Montréal and Centre de Recherche, Hôpital Maisonneuve Rosemont, Montréal, QC, H1T 2M4, Canada.
9
Deparment of Medicine, McGill University, Montreal, H4A 3J1, QC, Canada.
10
Department of Oncology, McGill University, Montreal, QC, H4A 3T2, Canada.
11
Division of Experimental Medicine, McGill University, Montreal, QC, H3A 1A3, Canada.
12
Department of Microbiology and Immunology, McGill University, Montreal, QC, H3A 2B4, Canada.
13
Institut de Recherches Cliniques de Montréal, IRCM, Montréal, QC, H2W 1R7, Canada. Tarik.Moroy@ircm.qc.ca.
14
Division of Experimental Medicine, McGill University, Montreal, QC, H3A 1A3, Canada. Tarik.Moroy@ircm.qc.ca.
15
Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC, H3C 3J7, Canada. Tarik.Moroy@ircm.qc.ca.

Abstract

GFI1 is a transcriptional regulator expressed in lymphoid cells, and an "oncorequisite" factor required for development and maintenance of T-lymphoid leukemia. GFI1 deletion causes hypersensitivity to ionizing radiation, for which the molecular mechanism remains unknown. Here, we demonstrate that GFI1 is required in T cells for the regulation of key DNA damage signaling and repair proteins. Specifically, GFI1 interacts with the arginine methyltransferase PRMT1 and its substrates MRE11 and 53BP1. We demonstrate that GFI1 enables PRMT1 to bind and methylate MRE11 and 53BP1, which is necessary for their function in the DNA damage response. Thus, our results provide evidence that GFI1 can adopt non-transcriptional roles, mediating the post-translational modification of proteins involved in DNA repair. These findings have direct implications for treatment responses in tumors overexpressing GFI1 and suggest that GFI1's activity may be a therapeutic target in these malignancies.

PMID:
29651020
PMCID:
PMC5897347
DOI:
10.1038/s41467-018-03817-5
[Indexed for MEDLINE]
Free PMC Article

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