Mismatch repair provides a security patch for translesion synthesis

Tsaalbi-Shtylik et al. reveal that DNA mismatch repair (MMR) proteins suppress UV-induced mutagenesis by removing nucleotides introduced by error-prone DNA polymerases.

The MMR pathway is best known for its role in correcting the rare mistakes of replicative DNA polymerases. However, the MMR proteins Msh2 and Msh6 have also been implicated in preventing the introduction of DNA mutations following exposure to low, physiological doses of UV light. UV-damaged nucleotides can’t undergo base pairing and are therefore not replicated by normal DNA polymerases. This results in patches of single-stranded DNA that can be filled in by specialized DNA polymerases in a process called translesion synthesis (TLS). These polymerases are error prone, however, so they frequently incorporate incorrect nucleotides opposite the photo-damaged nucleotide.

Tsaalbi-Shtylik et al. found that Msh2 and Msh6 recognize the incorrect nucleotides introduced by TLS opposite photolesions and trigger their removal, regenerating patches of single-stranded DNA around photo-damaged nucleotides. These patches induced the Chk1 DNA damage signaling pathway that arrests cells in S phase. If the single-stranded patches weren’t filled in before the subsequent S phase, they were converted to double-strand breaks that initiated apoptosis.

In the absence of Msh2/Msh6, nucleotides incorrectly incorporated by TLS remained in place, reducing checkpoint activation and cell death but introducing an increased number of DNA mutations. Patients with Lynch syndrome, who inherit mutations in MMR genes, may therefore suffer a high incidence of colorectal cancers because their intestinal cells are susceptible to genotoxic insults that cause similar damage to UV light. Senior author Niels de Wind now wants to investigate whether other MMR proteins are also involved in this “post-TLS” repair pathway.