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Nucleic Acids Research 2004 32(18):5486-5498; doi:10.1093/nar/gkh872
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Published online 12 October 2004

Nucleic Acids Research, Vol. 32 No. 18 © Oxford University Press 2004; all rights reserved

Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by short-patch repair both in proliferating and growth-arrested cells

Mansour Akbari, Marit Otterlei, Javier Peña-Diaz, Per Arne Aas, Bodil Kavli, Nina B. Liabakk, Lars Hagen, Kohsuke Imai1, Anne Durandy1, Geir Slupphaug and Hans E. Krokan*

Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway and 1 Institut National de la Santé et de la Recherche Médicale Unité 429, Hôpital Necker-Enfants Malades, 75015 Paris, France

* To whom correspondence should be addressed. Tel: +47 73598695; Fax: +47 73598801; Email: hans.krokan{at}medisin.ntnu.no

Received June 25, 2004; Revised and Accepted September 17, 2004

Nuclear uracil-DNA glycosylase UNG2 has an established role in repair of U/A pairs resulting from misincorporation of dUMP during replication. In antigen-stimulated B-lymphocytes UNG2 removes uracil from U/G mispairs as part of somatic hypermutation and class switch recombination processes. Using antibodies specific for the N-terminal non-catalytic domain of UNG2, we isolated UNG2-associated repair complexes (UNG2-ARC) that carry out short-patch and long-patch base excision repair (BER). These complexes contain proteins required for both types of BER, including UNG2, APE1, POLß, POL{delta}, XRCC1, PCNA and DNA ligase, the latter detected as activity. Short-patch repair was the predominant mechanism both in extracts and UNG2-ARC from proliferating and less BER-proficient growth-arrested cells. Repair of U/G mispairs and U/A pairs was completely inhibited by neutralizing UNG-antibodies, but whereas added recombinant SMUG1 could partially restore repair of U/G mispairs, it was unable to restore repair of U/A pairs in UNG2-ARC. Neutralizing antibodies to APE1 and POLß, and depletion of XRCC1 strongly reduced short-patch BER, and a fraction of long-patch repair was POLß dependent. In conclusion, UNG2 is present in preassembled complexes proficient in BER. Furthermore, UNG2 is the major enzyme initiating BER of deaminated cytosine (U/G), and possibly the sole enzyme initiating BER of misincorporated uracil (U/A).


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