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J. Biol. Chem., Vol. 278, Issue 48, 47937-47945, November 28, 2003

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Defective Human MutY Phosphorylation Exists in Colorectal Cancer Cell Lines with Wild-type MutY Alleles^*

Antony R. Parker, Robert N. O'Meally, Fikret Sahin, Gloria H. Su¶, Frederick K. Racke, William G. Nelson¶||, Theodore L. DeWeese¶, and James R. Eshleman¶**

From the Departments of Pathology, ^¶Oncology, Urology and ^||Pharmacology and Medicine, The Johns Hopkins University, Baltimore, Maryland 21205

Oxidative DNA damage can generate a variety of cytotoxic DNA lesions such as 8-oxoguanine (8-oxoG), which is one of the most mutagenic bases formed from oxidation of genomic DNA because 8-oxoG can readily mispair with either cytosine or adenine. If unrepaired, further replication of A·8-oxoG mispairs results in C:G to A:T transversions, a form of genomic instability. We reported previously that repair of A·8-oxoG mispairs was defective and that 8-oxoG levels were elevated in several microsatellite stable human colorectal cancer cell lines lacking MutY mutations (human MutY homolog gene, hmyh, MYH MutY homolog protein). In this report, we provide biochemical evidence that the defective repair of A·8-oxoG may be due, at least in part, to defective phosphorylation of the MutY protein in these cell lines. In MutY-defective cell extracts, but not extracts with functional MutY, A·8-oxoG repair was increased by incubation with protein kinases A and C (PKA and PKC) and caesin kinase II. Treatment of these defective cells, but not cells with functional MutY, with phorbol-12-myristate-13-acetate also increased the cellular A·8-oxoG repair activity and decreased the elevated 8-oxoG levels. We show that MutY is serine-phosphorylated in vitro by the action of PKC and in the MutY-defective cells by phorbol-12-myristate-13-acetate but that MutY is already phosphorylated at baseline in proficient cell lines. Finally, using antibody-isolated MutY protein, we show that MutY can be directly phosphorylated by PKC that directly increases the level of MutY catalyzed A·8-oxoG repair.

Received for publication, June 20, 2003 , and in revised form, August 15, 2003.

^* This work was supported by the Grant R01CA81439 from the National Institutes of Health (to J. R. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: The Johns Hopkins University, School of Medicine, Dept. of Pathology, 720 Rutland Ave., 632 Ross Bldg., Baltimore, MD 21205. Tel.: 410-955-3511; Fax: 410-614-0671; E-mail: jeshlema{at}jhmi.edu.

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