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J. Biol. Chem., Vol. 279, Issue 2, 859-865, January 9, 2004

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Lesion Bypass by Human DNA Polymerase µ Reveals a Template-dependent, Sequence-independent Nucleotidyl Transferase Activity^*

Shay Covo, Luis Blanco, and Zvi Livneh¶

From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel and the Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma, 28049 Madrid, Spain

DNA polymerase µ (pol µ), which is related to terminal deoxynucleotidyl transferase and DNA polymerase , is thought to be involved in non-homologous end joining and V(D)J recombination. Pol µ is induced by ionizing radiation and exhibits low fidelity. Analysis of translesion replication by purified human pol µ revealed that it bypasses a synthetic abasic site with high efficiency, using primarily a misalignment mechanism. It can also replicate across two tandem abasic sites, using the same mechanism. Pol µ extends primers whose 3'-terminal nucleotides are located opposite the abasic site. Most remarkably, this extension occurs via a mode of nucleotidyl transferase activity, which does not depend on the sequence of the template. This is not due to simple terminal nucleotidyl transferase activity, because pol µ is unable to add dNTPs to an oligo(dT)₂₉ primer or to a blunt end duplex oligonucleotide under standard conditions. Thus, pol µ is a dual mode DNA-synthesizing enzyme, which can act as either a classical DNA polymerase or as a non-canonical, template-dependent, but sequence-independent nucleotidyl transferase. To our knowledge, this is the first report on a DNA-synthesizing enzyme with such properties. These activities may be required for its function in non-homologous end joining in the processing of DNA ends prior to ligation.

Received for publication, September 22, 2003 , and in revised form, October 27, 2003.

^* This research was supported by Israel Science Foundation Grant 78/00. 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.

^¶ Incumbent of The Maxwell Ellis Professorial Chair in Biomedical Research and to whom all correspondence should be addressed. Tel.: 972-8-934-3203; Fax: 972-8-934-4169; E-mail: zvi.livneh{at}weizmann.ac.il.

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