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J. Biol. Chem., Vol. 280, Issue 32, 29030-29037, August 12, 2005

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DNA Joint Dependence of Pol X Family Polymerase Action in Nonhomologous End Joining^*

James M. Daley, Renee L. Vander Laan, Aswathi Suresh, and Thomas E. Wilson¶

From the Graduate Program in Cellular and Molecular Biology and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602

DNA double strand breaks (DSBs) can be rejoined directly by the nonhomologous end-joining (NHEJ) pathway of repair. Nucleases and polymerases are required to promote accurate NHEJ when the terminal bases of the DSB are damaged. The same enzymes also participate in imprecise rejoining and joining of incompatible ends, important mutagenic events. Previous work has shown that the Pol X family polymerase Pol4 is required for some but not all NHEJ events that require gap filling in Saccharomyces cerevisiae. Here, we systematically analyzed DSB end configurations and found that gaps on both strands and overhang polarity are the principal factors that determine whether a joint requires Pol4. DSBs with 3'-overhangs and a gap on each strand strongly depended on Pol4 for repair, DSBs with 5'-overhangs of the same sequence did not. Pol4 was not required when 3'-overhangs contained a gap on only one strand, however. Pol4 was equally required at 3'-overhangs of all lengths within the NHEJ-dependent range but was dispensable outside of this range, indicating that Pol4 is specific to NHEJ. Loss of Pol4 did not affect the rejoining of DSBs that utilized a recessed microhomology or DSBs bearing 5'-hydroxyls but no gap. Finally, mammalian Pol X polymerases were able to differentially complement a pol4 mutation depending on the joint structure, demonstrating that these polymerases can participate in yeast NHEJ but with distinct properties.

Received for publication, May 13, 2005 , and in revised form, June 14, 2005.

^* This work was supported by the Pew Scholars Program in the Biomedical Sciences of the Pew Charitable Trusts and Public Health Service Grant CA90911 (to T. E. W.) and by a University of Michigan Rackham predoctoral fellowship (to J. M. D.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

^¶ To whom correspondence should be addressed: Dept. of Pathology, University of Michigan Medical School, Medical Science I M4214/0602, 1301 Catherine Rd., Ann Arbor, MI 48109-0602. Tel.: 734-936-1887; Fax: 734-763-6476; E-mail: wilsonte{at}umich.edu.

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