Int J Biochem Mol Biol 2011;2(2):138-145

Original Article
Differential DNA damage responses in p53 proficient and deficient cells:
cisplatin-induced nuclear import of XPA is independent on ATR checkpoint in
p53-deficient lung cancer cells

Zhengke Li, Phillip R. Musich, Yue Zou

Department of Biochemistry and Molecular Biology East Tennessee State University, J.H Quillen College of Medicine, Johnson City,
Tennessee 37614

Received March 18, 2011; accepted March 23, 2011; Epub March 25, 2011; published April 30, 2011

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
BJ normal fibroblasts and 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 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. (IJBMB1103002).

Keywords: DNA damage checkpoints, p53, Nucleotide excision repair (NER), ataxia telangiectasia, Xeroderma pigmentosum group A

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Address all correspondence to:
Yue Zou, MD, PhD
East Tennessee State University
James H. Quillen College of Medicine
Department of Biochemistry and Molecular Biology
Johnson City, TN 37614
Phone: (423) 439-2124
FAX: (423) 439-2030