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p12(DOC-1), a growth suppressor, associates with DNA polymerase alpha/primase

  1. Author:
    Matsuo, K.
    Shintani, S.
    Tsuji, T.
    Nagata, E.
    Lerman, M.
    McBride, J.
    Nakahara, Y.
    Ohyama, H.
    Todd, R.
    Wong, D. T. W.

  2. Author Address

    Wong DTW Harvard Univ, Sch Dent Med, Div Oral Pathol, Lab Mol Pathol 188 Longwood Ave Boston, MA 02115 USA Harvard Univ, Sch Dent Med, Div Oral Pathol, Lab Mol Pathol Boston, MA 02115 USA Harvard Univ, Sch Dent Med, Lab Oral & Maxillofacial Surg Boston, MA 02115 USA NCI, Immunobiol Lab, DBS, Frederick Canc Res & Dev Ctr Frederick, MD 21702 USA
    1. Year: 2000
  2. Journal: Faseb Journal
    1. 14
    2. 10
    3. Pages: 1318-1324
  4. Type of Article: Article
  1. Abstract:

    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 alpha/primase (pol-alpha: primase) in vitro and in cells. The pol-alpha: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-alpha:primase was examined using in vitro DNA replication assays. Using the SV40 DNA replication assay, p12(DOC-1) suppresses DNA replication, leveling at similar to 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-alpha: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-alpha:primase. p12(DOC-1) suppresses CDK2-mediated phosphorylation of pol-alpha:primase. These data support a role of p12(DOC-1) as a regulator of DNA replication by direct inhibition of pol-alpha:primase or by negatively regulating the CDK2-mediated phosphorylation of pol-alpha:primase. [References: 22]

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