QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.020446v1 69/5/1748    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, X. Articles by Howell, S. B. Search for Related Content PubMed PubMed Citation Articles by Lin, X. Articles by Howell, S. B.

Human REV1 Modulates the Cytotoxicity and Mutagenicity of Cisplatin in Human Ovarian Carcinoma Cells

Department of Medicine and the Moores University of California at San Diego Cancer Center, University of California, San Diego, La Jolla, California

REV1 interacts with Y-type DNA polymerases (Pol) and Pol to bypass many types of adducts that block the replicative DNA polymerases. This pathway accounts for many of the mutations induced by cisplatin (cis-diamminedichloroplatinium II, DDP). This study sought to determine how increasing human REV1 (hREV1) affects the cytotoxicity and mutagenicity of DDP. Human ovarian carcinoma 2008 cells were transfected with an hREV1 expression vector and 4 sublines developed in which the hREV1 mRNA level was increased by 6.3- to 23.4-fold and hREV1 protein by 2.7- to 6.2-fold. The sublines were 1.3- to 1.7-fold resistant to the cytotoxic effect of DDP and 2.3- to 5.1-fold hypersensitive to the mutagenic effect of DDP. The hREV1-transfected sublines were 1.5- to 1.8-fold better than the parental 2008 cells at managing DDP adducts as assessed by their ability to express Renilla reniformis luciferase from a vector that had been extensively loaded with DDP adducts before transfection. Increased hREV1 expression was associated with a 1.5-fold increase in the rate at which the whole population acquired resistance to DDP during sequential cycles of drug exposure. Increasing the abundance of hREV1 thus resulted in both resistance to DDP and a significant elevation in DDP-induced mutagenicity. This was accompanied by an enhanced capacity to synthesize a functional protein from a DDP-damaged gene and, most importantly, by more rapid development of resistance during sequential cycles of DDP exposure that mimic clinical schedules of DDP administration. We conclude that hREV1-dependent processes are important determinants of DDP-induced genomic instability and the development of resistance.

Address correspondence to: Dr. Stephen B. Howell, Moores UCSD Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819. E-mail: showell{at}ucsd.edu

This article has been cited by other articles:

				L. S. Waters, B. K. Minesinger, M. E. Wiltrout, S. D'Souza, R. V. Woodruff, and G. C. Walker Eukaryotic Translesion Polymerases and Their Roles and Regulation in DNA Damage Tolerance Microbiol. Mol. Biol. Rev., March 1, 2009; 73(1): 134 - 154. [Abstract] [Full Text] [PDF]

				J. A. Brown, S. A. Newmister, K. A. Fiala, and Z. Suo Mechanism of double-base lesion bypass catalyzed by a Y-family DNA polymerase Nucleic Acids Res., July 1, 2008; 36(12): 3867 - 3878. [Abstract] [Full Text] [PDF]