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; Tarik Möröy

doi:10.1038/s41467-018-03817-5

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, Tarik Möröy

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

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.

Original language	English
Article number	1418
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03817-5
Publication status	Published - Dec 1 2018

Bibliographical note

Funding Information:
We thank: The staff of the IRCM Animal Facility, microscopy platform and Flow Cytometry facilities; Denis Faubert and the IRCM Proteomics discovery platform; Sylvie Lavallée and the staff of the Quebec Leukemia Cell Bank and Ludivine Litzler for discussion and suggestions. This work was supported by a CIHR (Canadian Institutes of Health Research) Foundation grant (FGN-148372) and a Canada Research Chair Tier 1 to T.M. C.V. was funded by a post-doctoral fellowship from FRQS (Fonds de Recherche en Santé du Québec) and by a post-doctoral fellowship from CIHR.

Publisher Copyright:
© 2018 The Author(s).

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Vadnais, C., Chen, R., Fraszczak, J., Yu, Z., Boulais, J., Pinder, J., Frank, D., Khandanpour, C., Hébert, J., Dellaire, G., Côté, J. F., Richard, S., Orthwein, A., Drobetsky, E., & Möröy, T. (2018). GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1. Nature Communications, 9(1), Article 1418. https://doi.org/10.1038/s41467-018-03817-5

Vadnais, C, Chen, R, Fraszczak, J, Yu, Z, Boulais, J, Pinder, J, Frank, D, Khandanpour, C, Hébert, J, Dellaire, G, Côté, JF, Richard, S, Orthwein, A, Drobetsky, E & Möröy, T 2018, 'GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1', Nature Communications, vol. 9, no. 1, 1418. https://doi.org/10.1038/s41467-018-03817-5

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N2 - 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.

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

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