Premium
Cell cycle‐specific UNG2 phosphorylations regulate protein turnover, activity and association with RPA
Author(s) -
Hagen Lars,
Kavli Bodil,
Sousa Mirta ML,
Torseth Kathrin,
Liabakk Nina B,
Sundheim Ottar,
PeňaDiaz Javier,
Otterlei Marit,
Hørning Ole,
Jensen Ole N,
Krokan Hans E,
Slupphaug Geir
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601958
Subject(s) - norwegian , library science , cancer , medicine , computer science , philosophy , linguistics
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.