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

Charles Vadnais,Riyan Chen,Jennifer Fraszczak,Elliot Drobetsky,Stéphane Richard,Jordan Pinder,Daria Frank,Cyrus Khandanpour,Jean-François Côté,Josée Hébert,Graham Dellaire,Alexandre Orthwein,Jonathan Boulais,Zhenbao Yu,Tarik Möröy

doi:10.1038/s41467-018-03817-5

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.

Highlights

GFI1 is a transcriptional regulator expressed in lymphoid cells, and an “oncorequisite” factor required for development and maintenance of T-lymphoid leukemia
We propose that GFI1 is required for proper interaction between Protein arginine methyltransferase 1 (PRMT1) and both MRE11 and 53BP1, and efficient arginine dimethylation of these latter two proteins on their GAR motifs, prior to the occurrence of DNA damage, priming them for an optimally rapid response to genotoxic stress
We note that our results showing defective homologous recombination (HR)-directed repair and radiosensitivity in Gfi1-deficient cells are similar to those obtained in previous studies using cells expressing a nonmethylatable MRE11 with arginine to lysine (R/K) replacements in its GAR motif[19]

Summary

Introduction

GFI1 is a transcriptional regulator expressed in lymphoid cells, and an “oncorequisite” factor required for development and maintenance of T-lymphoid leukemia. 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. The cellular response to DSBs leading to HR is triggered via recruitment of the trimeric MRN complex, composed of the proteins MRE11, RAD50, and NBS1, to sites of damage This complex mediates recruitment of the ataxia telangiectasia mutated (ATM) serine/threonine kinase, which becomes activated by monomerization and auto-phosphorylation[5,8,9]. PRMT1 targets MRE11 as well as 53BP1, both of which are critical for DNA repair pathway choice: MRE11 by initiating DNA end resection promoting HR, and 53BP1 by inhibiting inappropriate resection of DNA ends during G1 to favor NHEJ16,18

Methods

Results

Conclusion