HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 21, 15330-15340, May 25, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/21/15330    most recent M610356200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, S. Articles by Lee, M. Y. W. T. Search for Related Content PubMed PubMed Citation Articles by Zhang, S. Articles by Lee, M. Y. W. T. Social Bookmarking                      What's this?

A Novel DNA Damage Response

RAPID DEGRADATION OF THE p12 SUBUNIT OF DNA POLYMERASE ^*

From the Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595

Mammalian DNA polymerase (Pol) is essential for DNA replication. It consists of four subunits, p125, p50, p68, and p12. We report the discovery that the p12 subunit is rapidly degraded in cultured human cells by DNA damage or replication stress brought about by treatments with UV, methyl methanesulfonate, hydroxyurea, and aphidicolin. The degradation of p12 is due to an accelerated rate of proteolysis that is inhibited by the proteasome inhibitors, MG132 and lactacystin. UV treatment converts Pol in vivo to the three-subunit form lacking p12. This was demonstrated by its isolation using immunoaffinity chromatography. The three-subunit enzyme retains activity on poly(dA)/oligo(dT) templates but is impaired in its ability to extend singly primed M13 templates, clearly indicating that its in vivo functions are likely to be compromised. This transformation of Pol by modification of its quaternary structure is reversible in vitro by the addition of the p12 subunit and could represent a novel in vivo mechanism for the modulation of Pol function. UV and hydroxyurea-triggered p12 degradation is blocked in ATR^–/– cells but not in ATM^–/– cells, thereby demonstrating that p12 degradation is regulated by ATR, the apical kinase that regulates the damage response in S-phase. These findings reveal a novel addition to the cellular repertoire of DNA damage responses that also impacts our understanding of the role of Pol in both DNA replication and DNA repair.

Received for publication, November 7, 2006 , and in revised form, February 16, 2007.

^* This work was supported by National Institutes of Health Grant GM31973 and Philip Morris USA Inc., Philip Morris International. 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.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595. Tel.: 914-594-4070; Fax: 914-594-4058; E-mail: Marietta_Lee{at}NYMC.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				X. Meng, Y. Zhou, S. Zhang, E. Y. C. Lee, D. N. Frick, and M. Y. W. T. Lee DNA damage alters DNA polymerase {delta} to a form that exhibits increased discrimination against modified template bases and mismatched primers Nucleic Acids Res., February 1, 2009; 37(2): 647 - 657. [Abstract] [Full Text] [PDF]

				N. Selak, C. Z. Bachrati, I. Shevelev, T. Dietschy, B. van Loon, A. Jacob, U. Hubscher, J. D. Hoheisel, I. D. Hickson, and I. Stagljar The Bloom's syndrome helicase (BLM) interacts physically and functionally with p12, the smallest subunit of human DNA polymerase {delta} Nucleic Acids Res., September 1, 2008; 36(16): 5166 - 5179. [Abstract] [Full Text] [PDF]