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

被引：44

作者：

Vadnais, Charles ^{[1
]}

Chen, Riyan ^{[1
]}

Fraszczak, Jennifer ^{[1
]}

Yu, Zhenbao ^{[2
]}

Boulais, Jonathan ^{[1
]}

Pinder, Jordan ^{[3
,4
]}

Frank, Daria ^{[5
]}

Khandanpour, Cyrus ^{[5
]}

Hebert, Josee ^{[6
,7
,8
]}

Dellaire, Graham ^{[3
,4
]}

Cote, Jean-Francois ^{[1
,9
,10
]}

Richard, Stephane ^{[2
,11
,12
,13
]}

Orthwein, Alexandre ^{[2
,12
,13
,14
]}

Drobetsky, Elliot ^{[9
,10
]}

Moroy, Tarik ^{[1
,13
,15
]}

机构：

[1] IRCM, Montreal, PQ H2W 1R7, Canada

[2] Jewish Gen Hosp, Lady Davis Inst Med Res, Segal Canc Ctr, Montreal, PQ H3T 1E2, Canada

[3] Dalhousie Univ, Dept Pathol, Halifax, NS B3H 4R2, Canada

[4] Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS B3H 4R2, Canada

[5] Univ Hosp, Dept Hematol, D-45147 Essen, Germany

[6] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada

[7] Maisonneuve Rosemont Hosp, Div Hematol Oncol, Montreal, PQ H1T 2M4, Canada

[8] Maisonneuve Rosemont Hosp, Quebec Leukemia Cell Bank, Montreal, PQ H1T 2M4, Canada

[9] Univ Montreal, Dept Med, Montreal, PQ H1T 2M4, Canada

[10] Hop Maison Neuve Rosemont, Ctr Rech, Montreal, PQ H1T 2M4, Canada

[11] McGill Univ, Dept Med, Montreal, PQ H4A 3J1, Canada

[12] McGill Univ, Dept Oncol, Montreal, PQ H4A 3T2, Canada

[13] McGill Univ, Div Expt Med, Montreal, PQ H3A 1A3, Canada

[14] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada

[15] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ H3C 3J7, Canada

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

加拿大健康研究院;

关键词：

DOUBLE-STRAND BREAKS; T-CELL DEATH; ARGININE METHYLATION; DAMAGE RESPONSE; HOMOLOGOUS RECOMBINATION; ATM ACTIVATION; GAR MOTIF; PHOSPHORYLATION; MRE11-RAD50-NBS1; DIFFERENTIATION;

D O I：

10.1038/s41467-018-03817-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

共 48 条

[1] 53BP1 oligomerization is independent of its methylation by PRMT1 [J].