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Molecular and Cellular Biology, December 2009, p. 6206-6219, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00503-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Alo Ray,1* Safita N. Mir,1 Gulzar Wani,1 Qun Zhao,1 Aruna Battu,1 Qianzheng Zhu,1 Qi-En Wang,1 and Altaf A. Wani1,2,3*

Department of Radiology,1 Department of Molecular and Cellular Biochemistry,2 Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 432103

Received 17 April 2009/ Returned for modification 2 June 2009/ Accepted 18 September 2009

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.

* Corresponding author. Mailing address: 460 West 12th Avenue, Columbus, OH 43210. Phone: (614) 292-9015. Fax: (614) 292-9102. E-mail for Altaf A. Wani: wani.2{at}osu.edu. E-mail for Alo Ray: ray.275{at}osu.edu

{triangledown} Published ahead of print on 5 October 2009.

Molecular and Cellular Biology, December 2009, p. 6206-6219, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00503-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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