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  • The EMBO Journal (2008) 27, 51 - 61
  • doi:10.1038/sj.emboj.7601958

Published online: 13 December 2007

Cell cycle-specific UNG2 phosphorylations regulate protein turnover, activity and association with RPAEMBO Open

Lars Hagen1, Bodil Kavli1, Mirta M L Sousa1, Kathrin Torseth1, Nina B Liabakk1, Ottar Sundheim1, Javier Pen carona-Diaz1,a, Marit Otterlei1, Ole Hørning2, Ole N Jensen2, Hans E Krokan1 and Geir Slupphaug1

  1. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
  2. Protein Research Group, Department of Biochemistry & Molecular Biology, University of Southern Denmark, Odense M, Denmark

Correspondence to:

Geir Slupphaug, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Erling Skjalgssons gt 1, Trondheim 7006, Norway. Tel.: +47 91825455; Fax: +47 72576400; E-mail: geir.slupphaug@ntnu.no

aPresent address: Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, Zurich 8057, Switzerland

Received 20 July 2007; Accepted 22 November 2007

Human UNG2 is a multifunctional glycosylase that removes uracil near replication forks and in non-replicating DNA, and is important for affinity maturation of antibodies in B cells. How these diverse functions are regulated remains obscure. Here, we report three new phosphoforms of the non-catalytic domain that confer distinct functional properties to UNG2. These are apparently generated by cyclin-dependent kinases through stepwise phosphorylation of S23, T60 and S64 in the cell cycle. Phosphorylation of S23 in late G1/early S confers increased association with replication protein A (RPA) and replicating chromatin and markedly increases the catalytic turnover of UNG2. Conversely, progressive phosphorylation of T60 and S64 throughout S phase mediates reduced binding to RPA and flag UNG2 for breakdown in G2 by forming a cyclin E/c-myc-like phosphodegron. The enhanced catalytic turnover of UNG2 p-S23 likely optimises the protein to excise uracil along with rapidly moving replication forks. Our findings may aid further studies of how UNG2 initiates mutagenic rather than repair processing of activation-induced deaminase-generated uracil at Ig loci in B cells.

  • Keywords:

    • cell cycle,
    • phosphodegron phosphorylation,
    • replication forks,
    • uracil-DNA glycosylase

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The EMBO Journal is published by Nature Publishing Group on behalf of European Molecular Biology Organization