Abstract
Accessibility within chromatin is an important factor in the prompt removal of UV-induced DNA damage by nucleotide excision repair (NER). Chromatin remodeling by the SWI/SNF complex has been shown to play an important modulating role in NER in vitro and yeast in vivo. Nevertheless, the molecular basis of cross-talk between SWI/SNF and NER in mammalian cells is not fully understood. Here, we show that knockdown of Brg1, the ATPase subunit of SWI/SNF, negatively affects the elimination of cyclobutane pyrimidine dimers (CPD), but not of pyrimidine (6, 4)pyrimidone photoproducts (6-4PP) following UV irradiation of mammalian cells. Brg1-deficient cells exhibit a lower chromatin relaxation as well as impaired recruitment of downstream NER factors, XPG and PCNA, to UV lesions. However, the assembly of upstream NER factors, DDB2 and XPC, at the damage site was unaffected by Brg1 knockdown. Interestingly, Brg1 interacts with XPC within chromatin and is recruited to UV-damaged sites in a DDB2- and XPC-dependent manner. Also, postirradiation decrease of XPC levels occurred more rapidly in Brg1-deficient than normal cells. Conversely, XPC transcription remained unaltered upon Brg1 knockdown indicating that Brg1 affects the stability of XPC protein following irradiation. Thus, Brg1 facilitates different stages of NER by initially modulating UV-induced chromatin relaxation and stabilizing XPC at the damage sites, and subsequently stimulating the recruitment of XPG and PCNA to successfully culminate the repair.
Highlights
nucleotide excision repair (NER) is a versatile DNA repair pathway that can remove a broad range of structurally unrelated lesions including UV-induced bulky DNA adducts cyclobutane pyrimidine dimers (CPD) and pyrimidine[]pyrimidone photoproducts (6-4PP)
Brg1 Is Required for Efficient Removal of UV-induced DNA Damage CPD but Not 6-4PP—A few existing studies in vitro as well as in vivo imply that SWI/SNF chromatin remodeling complex is an indispensable factor in NER occurring within the context of chromatin [24, 25]
SWI/SNF ATP-dependent chromatin remodeling complex is an important player in DNA repair pathways including double strand break (DSB) repair, base excision repair (BER), and NER [2]
Summary
NER is a versatile DNA repair pathway that can remove a broad range of structurally unrelated lesions including UV-induced bulky DNA adducts cyclobutane pyrimidine dimers (CPD) and pyrimidine[]pyrimidone photoproducts (6-4PP). For the first time, that recruitment of Brg1 to UV-induced CPD depends on DDB2 and XPC, indicating that SWI/SNF functions downstream of damage recognition. Brg1 Is Required for Efficient Removal of UV-induced DNA Damage CPD but Not 6-4PP—A few existing studies in vitro as well as in vivo imply that SWI/SNF chromatin remodeling complex is an indispensable factor in NER occurring within the context of chromatin [24, 25].
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