Modulation of XPA Nuclear Accumulation by ATR Dependent Checkpoint Pathways in Response to UV Irradiation

Abstract

In response to DNA damage, mammalian cells activate various DNA repair pathways to remove DNA lesions and, meanwhile, halt cell cycle progression to allow time for repair. The nucleotide excision repair (NER) and the ATR-dependent cell cycle checkpoint activation are two major cellular responses initiated by UV irradiation. Here we demonstrate that the NER factor XPA accumulated in the nucleus following UV irradiation, and the event occurred in an ATR-dependent manner. Treatment of cells with ATR kinase inhibitors and transfection of cells with siRNA targeted to ATR both compromised the UV-induced XPA nuclear translocation. XPA nuclear accumulation was also disrupted in ATR-deficient cells as well as in cells expressing ATR-kinase dead, as observed by immunofluorescent microscopy and western blot. Moreover, we found that ATR is required for the UV-induced nuclear focus formation of XPA. Taken together, our results suggest that the ATR checkpoint pathway may modulate NER activity through the regulation of XPA redistribution in human cells upon UV irradiation.