Great leaps forward: translesion synthesis gets unstalled

One important question facing the field of DNA repair is: how does the cell sense and respond to the presence of DNA damage? Many sessions at this meeting discussed the potential signalling cascades that might contribute to this poorly understood process. There are many possible players, including some or all of the following: the DNA lesion itself, ‘naked’ single-stranded DNA, stalled replication and transcription complexes, MMR proteins bound to DNA damage, futile DNA repair cycles, protein kinases including DNA-PK and ATM, and cell-cycle regulatory proteins including p53, p73 and p21. Modrich presented evidence that MMR proteins act at an early step in this process: both hMutSα and hMutLα are required for DNA-damage-dependent phosphorylation of p537xhMutSα- and hMutLα-dependent phosphorylation of p53 in response to DNA methylator damage. Duckett, D.R. et al. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12384–12388Crossref | PubMed | Scopus (146)See all References7, and others have shown that hMutSα is required for the induction of apoptosis in response to certain alkylated DNA bases8xRole of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents. Hickman, M.J. and Samson, L.D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10764–10769Crossref | PubMed | Scopus (248)See all References8. Thus, eukaryotic MMR proteins might regulate directly or indirectly at least one branch of the DNA-damage-dependent signalling cascade. This is an important area for future studies and is likely to show significant progress between now and the next Mega-Meeting on DNA Repair and Mutagenesis.