Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Cell. 2010 Apr 16;141(2):255-67. doi: 10.1016/j.cell.2010.02.028.
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.
受损的 DNA 模板为复制叉提供了障碍，并可能导致基因组不稳定。在真核生物中，对受损 DNA 的容忍主要是通过 RAD6 途径介导的，该途径涉及 DNA 聚合酶持续因子 PCNA 的泛素化。虽然 PCNA 的单泛素化介导易错跨损伤合成（TLS），但多泛素化触发无错途径。人们认为这两个途径都发生在 S 期，以确保复制完成。然而，我们发现将 TLS 或无错途径限制在细胞周期的 G2/M 期，可有效地促进损伤容忍。因此，我们的发现表明，DNA 损伤容忍途径的两个分支在 S 期之外的染色体复制后都能有效地发挥作用。因此，我们提出 RAD6 途径作用于新重新启动的复制叉留下的单链缺口。
