Thread by @jasonwwong

Excited to share our latest preprint titled "Deficiency in DNA mismatch repair of methylation damage is a major mutational process in cancer" biorxiv.org/content/10.110… #Cancer #DNARepair

MMR is well known for its role in the repair of mismatched base pairs that escape proof-reading by replicative DNA polymerases. However, more than 4 mutational signatures have been associated with MMR deficient cancers. What are their underlying processes?

To find out what these processes might be, we carefully classified MMR deficient cancers (aka MSI cancers) from TCGA based on whether they are MutSα (mismatch recognition) or MutLα (nuclease) deficient.

Surprisingly, mutations from MutSα deficient cancers are almost completely contributed from a [C>T]pG rich signature (akin to Sig 6), whereas MutLα generately have both [C>T]pG and T>C mutations.

Using replication strand bias, we found that [C>T]pG in MutSα are replication independent, supporting that these mutations arose from 5mC deamination induced mismatches (i.e. methylation damage).

So why is MutSα important for repairing methylation damage? Isn't MBD4 responsible? Turns out that there is H3K36me3 dependent repair of methylation damage even in the absence of MBD4. Moreover, H3K36me3 is much more predicative of [C>T]pG mutation compared with MBD4 binding.

This suggests that MutSα is likely involved in the initial recognition of deamination induced mismatches and then facilitates the recruitment of MBD4 or also perhaps TDG for base excision repair.

Why are the mutational signatures from clonal expansion of MutSα deficient cell lines different? Turns out that their mutations mostly arise during replication as cell lines replicate too quickly for methylation damage to accumulate.

Despite all the literature and model systems to study MMR, it is remarkable that this function of MMR was more has only been uncovered from the analysis of cancer genomes! Thank you to those who have shared their data as always. And thank you for your hard work @FangHu_HKU