Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage

被引:84
作者
Hill, Sarah J. [1 ,2 ]
Rolland, Thomas [1 ,2 ,3 ]
Adelmant, Guillaume [1 ,4 ,5 ]
Xia, Xianfang [1 ,2 ,3 ]
Owen, Matthew S. [1 ,2 ,3 ]
Dricot, Amelie [1 ,2 ,3 ]
Zack, Travis I. [1 ,6 ]
Sahni, Nidhi [1 ,2 ,3 ]
Jacob, Yves [1 ,2 ,3 ,7 ,8 ,9 ]
Hao, Tong [1 ,2 ,3 ]
McKinney, Kristine M. [1 ,2 ]
Clark, Allison P. [1 ,2 ]
Reyon, Deepak [10 ,11 ,12 ]
Tsai, Shengdar Q. [10 ,11 ,12 ]
Joung, J. Keith [10 ,11 ,12 ]
Beroukhim, Rameen [1 ,6 ,13 ]
Marto, Jarrod A. [1 ,4 ,5 ]
Vidal, Marc [1 ,2 ,3 ]
Gaudet, Suzanne [1 ,2 ,3 ]
Hill, David E. [1 ,2 ,3 ]
Livingston, David M. [1 ,2 ]
机构
[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA
[3] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA
[4] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[5] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA
[6] Broad Inst, Cambridge, MA 02142 USA
[7] Inst Pasteur, Dept Virol, Unite Genet Mol Virus ARN, F-75015 Paris, France
[8] CNRS, UMR3569, F-75015 Paris, France
[9] Univ Paris Diderot, Unite Genet Mol Virus ARN, F-75015 Paris, France
[10] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA
[11] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA
[12] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[13] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA
基金
美国国家卫生研究院;
关键词
BRCA1 interaction screening; DNA damage; transcription; RNA-POLYMERASE-II; PLATINUM-BASED CHEMOTHERAPY; CELL-CYCLE; MMS22L-NFKBIL2; COMPLEX; CANCER SUSCEPTIBILITY; MMS22L-TONSL COMPLEX; TUMOR SUPPRESSORS; BREAST-CANCER; PROTEIN; GENOME;
D O I
10.1101/gad.241620.114
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
BRCA1 is a breast and ovarian tumor suppressor. Given its numerous incompletely understood functions and the possibility that more exist, we performed complementary systematic screens in search of new BRCA1 protein-interacting partners. New BRCA1 functions and/or a better understanding of existing ones were sought. Among the new interacting proteins identified, genetic interactions were detected between BRCA1 and four of the interactors: TONSL, SETX, TCEANC, and TCEA2. Genetic interactions were also detected between BRCA1 and certain interactors of TONSL, including both members of the FACT complex. From these results, a new BRCA1 function in the response to transcription-associated DNA damage was detected. Specifically, new roles for BRCA1 in the restart of transcription after UV damage and in preventing or repairing damage caused by stabilized R loops were identified. These roles are likely carried out together with some of the newly identified interactors. This new function may be important in BRCA1 tumor suppression, since the expression of several interactors, including some of the above-noted transcription proteins, is repeatedly aberrant in both breast and ovarian cancers.
引用
收藏
页码:1957 / 1975
页数:19
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