New Insights into the Roles of XPA and RPA in DNA Repair and Damage Responses

Yiyong      Liu; Yue      Zou

Abstract

Xeroderma pigmentosum group A (XPA) and replication protein A (RPA) are two essential proteins for nucleotide excision repair (NER), a DNA repair pathway that removes a large variety of bulky DNA lesions in cells. In addition to its role in NER, RPA also is required for almost all other cellular DNA metabolic pathways, such as DNA replication, recombination, and other repair pathways. Although both proteins have been extensively studied for more than a decade, efforts have been focused mostly on their roles in DNA damage recognition in NER and/or single-stranded DNA binding. Recent advance in understanding the cellular functions of XPA and RPA reveals novel activities of the proteins in DNA damage responses. Briefly, XPA was found to be recruited to a DNA damage site for repair after TFIIH binds. The protein is also able to recognize specific structures of undamaged DNA. In addition, a nuclear import of XPA occurs upon DNA damage and in an ataxia-telangiectasia mutated and Rad3-related (ATR)-dependent manner. Furthermore, XPA undergoes phosphorylation by ATR checkpoint, promoting cell survival in response to UV irradiation. For RPA, the protein was found to play a role in activation of DNA damage checkpoint apparatuses ATR and the Rad9/Rad1/Hus1 complex. RPA also undergoes hyperphosphorylation upon DNA damage, which induces structural changes of the protein. Finally the hyperphosphorylation appears to be involved in modulating the activities of RPA and, thus, the cellular processes in which it participates. Here the molecular mechanisms by which XPA and RPA function in DNA damage responses are discussed in light of our recent understandings.

Keywords: XPA, RPA, DNA damage, DNA repair, Checkpoint, Nucleotide excision repair

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