BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

CORC > 昆明动物研究所 > 昆明动物研究所 > 动物模型与人类重大疾病机理重点实验室 > 重大疾病机理的遗传学

	BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss
	Tu ZG 1; Zhuang XY 2; Yao YG 2; Zhang RG[*]1
刊名	MOLECULAR AND CELLULAR BIOLOGY
	2013
卷号	33 期号:9 页码:1819-1829
通讯作者	rzhang@wistar.org
合作状况	其它
英文摘要	Cellular senescence is an important tumor suppression mechanism. We have previously reported that both oncogene-induced dissociation of BRCA1 from chromatin and BRCA1 knockdown itself drive senescence by promoting formation of senescence-associated heterochromatin foci (SAHF). However, the molecular mechanism by which BRCA1 regulates SAHF formation and senescence is unclear. BRG1 is a chromatin-remodeling factor that interacts with BRCA1 and pRB. Here we show that BRG1 is required for SAHF formation and senescence induced by oncogenic RAS or BRCA1 loss. The interaction between BRG1 and BRCA1 is disrupted during senescence. This correlates with an increased level of chromatin-associated BRG1 in senescent cells. BRG1 knockdown suppresses the formation of SAHF and senescence, while it has no effect on BRCA1 chromatin dissociation induced by oncogenic RAS, indicating that BRG1 functions downstream of BRCA1 chromatin dissociation. Furthermore, BRG1 knockdown inhibits SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence in a DNA damage-independent manner. This effect depends upon BRG1's chromatin-remodeling activity as well as the interaction between BRG1 and pRB. Indeed, the interaction between BRG1 and pRB is enhanced during senescence. Chromatin immunoprecipitation analysis revealed that BRG1's association with the human CDKN2A and CDKN1A gene promoters was enhanced during senescence induced by oncogenic RAS or BRCA1 knockdown. Consistently, knockdown of pRB, p21(CIP1), and p16(INK4a), but not p53, suppressed SAHF formation induced by BRG1. Together, these studies reveal the molecular underpinning by which BRG1 acts downstream of BRCA1 to promote SAHF formation and senescence.
收录类别	SCI
资助信息	This work was supported by a NIH/NCI grant (R01CA160331toR.Z.) and, in part, by a DOD award (OC093420 to R.Z.). Support of core facil- ities used in this study was provided by Cancer Center Support Grant CA010815 to The Wistar Institute.
语种	英语
WOS记录号	WOS:000317273300012
公开日期	2013-05-09
内容类型	期刊论文
源URL	[http://159.226.149.42:8088/handle/152453/7419]
专题	昆明动物研究所_重大疾病机理的遗传学昆明动物研究所_动物模型与人类重大疾病机理重点实验室
作者单位	1.Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, USA 2.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan, China
推荐引用方式 GB/T 7714	Tu ZG,Zhuang XY,Yao YG,et al. BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss[J]. MOLECULAR AND CELLULAR BIOLOGY,2013,33(9):1819-1829.
APA	Tu ZG,Zhuang XY,Yao YG,&Zhang RG[*].(2013).BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss.MOLECULAR AND CELLULAR BIOLOGY,33(9),1819-1829.
MLA	Tu ZG,et al."BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss".MOLECULAR AND CELLULAR BIOLOGY 33.9(2013):1819-1829.