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p12^DOC-1, a growth suppressor, associates with DNA polymerase /primase

KOU MATSUO^*,1, SATORU SHINTANI^*,1, TAKANORI TSUJI^*, EMI NAGATA^*, MICHAEL LERMAN, JIM MCBRIDE^*, YUUJI NAKAHARA^*, HIROE OHYAMA^*, RANDY TODD and DAVID T. W. WONG^*2

^* Laboratory of Molecular Pathology, Division of Oral Pathology, and
Laboratory of Oral and Maxillofacial Surgery, Harvard University, School of Dental Medicine, Boston, Massachusetts 02115, USA; and
Laboratory of Immunobiology, DBS, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA

²Correspondence: Harvard University, School of Dental Medicine, 188 Longwood Ave., Boston, MA 02115, USA. E-mail: David_Wong{at}hms.harvard.edu

p12^DOC-1 is a growth suppressor identified and isolated from normal keratinocytes. Ectopic expression of p12^DOC-1 in squamous carcinoma cells led to the reversion of in vitro transformation phenotypes including anchorage independence, doubling time, and morphology. Here we report that p12^DOC-1 associates with DNA polymerase /primase (pol-:primase) in vitro and in cells. The pol-:primase binding domain in p12^DOC-1 is mapped to the amino-terminal six amino acid (MSYKPN). The biological effect of p12^DOC-1 on pol-:primase was examined using in vitro DNA replication assays. Using the SV40 DNA replication assay, p12^DOC-1 suppresses DNA replication, leveling at ~50%. Similar results were obtained using the M13 single-stranded DNA synthesis assay. Analysis of the DNA replication products revealed that p12^DOC-1 affects the initiation step, not the elongation phase. The p12^DOC-1 suppression of DNA replication is likely to be mediated either by a direct inhibitory effect on pol-:primase or by its effect on cyclin-dependent kinase 2 (CDK2), a recently identified p12^DOC-1-associated protein known to stimulate DNA replication by phosphorylating pol-:primase. p12^DOC-1 suppresses CDK2-mediated phosphorylation of pol-:primase. These data support a role of p12^DOC-1 as a regulator of DNA replication by direct inhibition of pol-:primase or by negatively regulating the CDK2-mediated phosphorylation of pol-:primase.—Matsuo, K., Shintani, S., Tsuji, T., Nagata, E., Lerman, M., McBride, J., Nakahara, Y., Ohyama, H., Todd, R., Wong, D. T. W. p12^DOC-1, a growth suppressor, associates with DNA polymerase /primase.

Key Words: pol-:primase complex • cell cycle regulator • DNA replication

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