Ubiquitination and deubiquitination of PCNA in response to stalling of the replication fork.
Following exposure of human cells to DNA damaging agents that block the progress of the replication fork, mono-ubiquitination of PCNA mediates the switch from replicative DNA polymerases to polymerases specialised for translesion synthesis. We have shown that this modification of PCNA is necessary for the survival of cells after UV-irradiation and methyl methanesulfonate, that it is independent of cell cycle checkpoint activation, and that it persists after UV damage has been removed. In this Extra-view, we compare the regulation and biological significance of PCNA ubiquitination following treatments with UV light and the replication inhibitor hydroxyurea. We show that ubiquitination persists after removal of the replication block in both cases. With UV however, the persistence of ubiquitinated PCNA correlates with disappearance of the PCNA deubiquitinating enzyme USP1, whereas this is not the case for HU. Prevention of PCNA ubiquitination sensitises the cells to killing by both UV and HU.
Brown
Stephanie
S
Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK.
Niimi
Atsuko
A
Lehmann
Alan R
AR
D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays
D018809:Proliferating Cell Nuclear Antigen; D008741:Methyl Methanesulfonate; D004259:DNA-Directed DNA Polymerase; D006918:Hydroxyurea