title: Differential DNA damage responses in p53 proficient and deficient cells: cisplatin-induced nuclear import of XPA is independent of ATR checkpoint in p53-deficient lung cancer cells.
abstract: Nucleotide excision repair (NER) and ataxia telangiectasia mutated (ATM)/ATR (ATM- and RAD3-related) DNA damage checkpoints are among the major pathways that affect the chemotherapeutic efficiency of the anticancer drug cisplatin. Xeroderma pigmentosum group A (XPA) protein plays a crucial role in NER including both global genome repair (GG-NER) and transcription-coupled repair (TC-NER) subpathways, and has been a potential target for improving cisplatin therapeutic effects. We report here that XPA translocates from the cytosol into the nucleus after DNA damage induced by UV irradiation and cisplatin, a mimetic of UV damage, in human cells with or without p53 deficiency. However, the damage-induced response of XPA nuclear import was significantly slower in p53-deficient cells than in p53-proficient cells. We also found that while XPA is imported into the nucleus upon cisplatin or UV damage in an ATR-dependent manner in p53-proficient A549 lung cancer cells, the ATR checkpoint pathway has no effect on the XPA nuclear import in p53-deficient H1299 lung cancer cells. Similarly, the XPA nuclear translocation is not regulated by ATM checkpoint or by p38MAPK/MK2 either. Our findings suggest that NER is independent on the major DNA damage checkpoint pathways in H1299 (p53(-/-)) cells and that DNA damage responses are mechanistically different between p53-proficient and p53-deficient cells. Our results also highlight the possibility of selectively targeting XPA nuclear import as a way to sensitize cisplatin anticancer activity, but targeting ATR/ATM-dependent checkpoints may not be helpful in killing p53-deficient cancer cells.
authors.affiliation: Department of Biochemistry and Molecular Biology East Tennessee State University, J.H Quillen College of Medicine, Johnson City, Tennessee 37614, USA.
authors.forename: Zhengke
authors.initials: Z
authors.lastname: Li
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Musich
authors.forename: Yue
authors.initials: Y
authors.lastname: Zou