Human SNF5/INI1, a component of the human SWI/SNF chromatin remodeling complex, promotes nucleotide excision repair by influencing ATM recruitment and downstream H2AX phosphorylation.
Recent studies have implicated the role of the SWI/SNF ATP-dependent chromatin remodeling complex in nuclear excision repair (NER), but the mechanism of its function has remained elusive. Here, we show that the human SWI/SNF component human SNF5 (hSNF5) interacts with UV damage recognition factor XPC and colocalizes with XPC at the damage site. Inactivation of hSNF5 did not affect the recruitment of XPC but affected the recruitment of ATM checkpoint kinase to the damage site and ATM activation by phosphorylation. Consequently, hSNF5 deficiency resulted in a defect in H2AX and BRCA1 phosphorylation at the damage site. However, recruitment of ATR checkpoint kinase to the damage site was not affected by hSNF5 deficiency, supporting that hSNF5 functions downstream of ATR. Additionally, ATM/ATR-mediated Chk2/Chk1 phosphorylation was not affected in hSNF5-depleted cells in response to UV irradiation, suggesting that the cell cycle checkpoint is intact in these cells. Taken together, the results indicate that the SWI/SNF complex associates with XPC at the damage site and thereby facilitates the access of ATM, which in turn promotes H2AX and BRCA1 phosphorylation. We propose that the SWI/SNF chromatin remodeling function is utilized to increase the DNA accessibility of NER machinery and checkpoint factors at the damage site, which influences NER and ensures genomic integrity.
Ray
Alo
A
Department of Radiology, The Ohio State University, Columbus, OH 43210, USA.
Mir
Safita N
SN
Wani
Gulzar
G
Zhao
Qun
Q
Battu
Aruna
A
Zhu
Qianzheng
Q
Wang
Qi-En
QE
Wani
Altaf A
AA
D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding / Q000528:radiation effects; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014466:Ultraviolet Rays
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C086984:XPC protein, human; D004247:DNA; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases