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

Charles Vadnais, Riyan Chen, Jennifer Fraszczak, Zhenbao Yu, Jonathan Boulais, Jordan Pinder, Daria Frank, Cyrus Khandanpour, Josée Hébert, Graham Dellaire, Jean-François Côté, Stéphane Richard, Alexandre Orthwein, Elliot Drobetsky and Tarik Möröy ()
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Charles Vadnais: Institut de Recherches Cliniques de Montréal, IRCM
Riyan Chen: Institut de Recherches Cliniques de Montréal, IRCM
Jennifer Fraszczak: Institut de Recherches Cliniques de Montréal, IRCM
Zhenbao Yu: Jewish General Hospital
Jonathan Boulais: Institut de Recherches Cliniques de Montréal, IRCM
Jordan Pinder: Dalhousie University
Daria Frank: University Hospital
Cyrus Khandanpour: University Hospital
Josée Hébert: Université de Montréal
Graham Dellaire: Dalhousie University
Jean-François Côté: Institut de Recherches Cliniques de Montréal, IRCM
Stéphane Richard: Jewish General Hospital
Alexandre Orthwein: Jewish General Hospital
Elliot Drobetsky: Université de Montréal and Centre de Recherche, Hôpital Maisonneuve Rosemont
Tarik Möröy: Institut de Recherches Cliniques de Montréal, IRCM

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03817-5

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