Document Detail


BRG1 is required for formation of senescence-associated heterochromatin foci induced by oncogenic RAS or BRCA1 loss.
MedLine Citation:
PMID:  23438604     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Zhigang Tu; Xinying Zhuang; Yong-Gang Yao; Rugang Zhang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-02-25
Journal Detail:
Title:  Molecular and cellular biology     Volume:  33     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-08     Completed Date:  2013-05-29     Revised Date:  2013-11-05    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1819-29     Citation Subset:  IM    
Affiliation:
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
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MeSH Terms
Descriptor/Qualifier:
BRCA1 Protein / genetics,  metabolism*
Cell Aging*
Cell Line
Cyclin-Dependent Kinase Inhibitor p16 / genetics,  metabolism
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism
DNA Helicases / genetics,  metabolism*
Gene Knockdown Techniques
Genes, ras
Heterochromatin / metabolism*
Humans
Nuclear Proteins / genetics,  metabolism*
Transcription Factors / genetics,  metabolism*
Tumor Suppressor Protein p53 / genetics,  metabolism
ras Proteins / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
CA010815/CA/NCI NIH HHS; R01 CA160331/CA/NCI NIH HHS; R01CA160331/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/BRCA1 Protein; 0/Cdkn1a protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Heterochromatin; 0/Nuclear Proteins; 0/Transcription Factors; 0/Tumor Suppressor Protein p53; EC 3.6.1.-/DNA Helicases; EC 3.6.1.-/SMARCA4 protein, human; EC 3.6.5.2/ras Proteins
Comments/Corrections

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