The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S phase.
Damaged DNA templates provide an obstacle to the replication fork and can cause genome instability. In eukaryotes, tolerance to damaged DNA is mediated largely by the RAD6 pathway involving ubiquitylation of the DNA polymerase processivity factor PCNA. Whereas monoubiquitylation of PCNA mediates error-prone translesion synthesis (TLS), polyubiquitylation triggers an error-free pathway. Both branches of this pathway are believed to occur in S phase in order to ensure replication completion. However, we found that limiting TLS or the error-free pathway to the G2/M phase of the cell-cycle efficiently promote lesion tolerance. Thus, our findings indicate that both branches of the DNA damage tolerance pathway operate effectively after chromosomal replication, outside S phase. We therefore propose that the RAD6 pathway acts on single-stranded gaps left behind newly restarted replication forks.
Karras
Georgios I
GI
Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Jentsch
Stefan
S
D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D053858:Metabolic Networks and Pathways; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D053484:RecQ Helicases / Q000378:metabolism; D016196:S Phase; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D054875:Ubiquitination
D018809:Proliferating Cell Nuclear Antigen; D029701:Saccharomyces cerevisiae Proteins; C471606:RAD6 protein, S cerevisiae; D044763:Ubiquitin-Conjugating Enzymes; C076225:RAD5 protein, S cerevisiae; C090472:SGS1 protein, S cerevisiae; D004265:DNA Helicases; D053484:RecQ Helicases