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| Subject Categories: Cell Cycle | Genome Stability & Dynamics |
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| The EMBO Journal
(2008) 27, 51–61, doi:10.1038/sj.emboj.7601958 Published online 13 December 2007 |
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| Cell cycle-specific UNG2 phosphorylations regulate protein turnover, activity and association with RPA EMBO Open |
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Lars Hagen1, Bodil Kavli1, Mirta M L Sousa1, Kathrin Torseth1, Nina B Liabakk1, Ottar Sundheim1, Javier Pe a-Diaz1, 3, Marit Otterlei1, Ole Hørning2, Ole N Jensen2, Hans E Krokan1 and Geir Slupphaug1
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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 To whom correspondence should be addressed 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 3 Present address: Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, Zurich 8057, Switzerland Received 20 July 2007; Accepted 22 November 2007; Published online 13 December 2007. |
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| Abstract |
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| 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. |
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| Keywords: cell cycle, phosphodegron phosphorylation, replication forks, uracil-DNA glycosylase |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated NEWS AND VIEWSAntibody diversity: one enzyme to rule them all Nature Medicine News and Views (01 Dec 2004) RESEARCHThe EMBO Journal Article SMUG1 is able to excise uracil from immunoglobulin genes: insight into mutation versus repair The EMBO Journal Article (08 Feb 2006) Post-replicative base excision repair in replication foci The EMBO Journal Article (01 Jul 1999) |
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