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Cell Cycle Regulation of the Human DNA Mismatch Repair Genes hMSH2, hMLH1, and hPMS2¹

Department of Human Oncology, University of Wisconsin, Madison, Wisconsin 53792 [M. M., M. T., E. O., J. E. L., T. W. D., C. W-V. P., D. A. B.], and DNA Repair and Molecular Carcinogenesis Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [S. A., T. W., R. F.]

Hereditary nonpolyposis colorectal cancer is a cancer susceptibility syndrome that has been found to be caused by mutations in any of several genes involved in DNA mismatch repair, including hMSH2, hMLH1, or hPMS2. Recent reports have suggested that hMSH2 and hMLH1 have a role in the regulation of the cell cycle. To determine if these genes are cell cycle regulated, we examined their mRNA and protein levels throughout the cell cycle in IMR-90 normal human lung fibroblasts. We demonstrate that the levels of hMSH2 mRNA and protein do not change appreciably throughout the cell cycle. Although hMLH1 mRNA levels remained constant, there was a modest (approximately 50%) increase in its protein levels during late G₁ and S phase. The levels of hPMS2 mRNA fluctuated (decreasing 50% in G₁ and increasing 50% in S phase), whereas hPMS2 protein levels increased 50% in late G₁ and S phase. Our data indicate that, at least in normal cells, the machinery responsible for the detection and repair of mismatched DNA bases is present throughout the cell cycle.

¹ This work was supported by U.S. Department of Energy Grant DE-FG02-93ER61707-05 (to D. A. B.) and NIH Grant CA67007 (to R. F.).

² To whom requests for reprints should be addressed, at Department of Human Oncology, University of Wisconsin, K4/626 Clinical Sciences Center, 600 Highland Avenue, Madison, WI 53792. Phone: (608) 262-4970; Fax: (608) 263-8613; E-mail: boothman@humonc.wisc.edu.

Received 8/21/96. Accepted 12/ 3/96.

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