Human PMS1-dependent non-canonical mismatch repair engages with MBD4 to repair methylated CpG deamination.

Spontaneous deamination of 5-methylcytosine creates T:G mismatches repaired by the MBD4 glycosylase, which physically cooperates with the MutLβ (MLH1-PMS1) and MutSα (MSH2-MSH6) complexes in a replication-independent, non-canonical branch of mismatch repair.

CpG dinucleotides are mutational hotspots because of spontaneous 5-methylcytosine deamination, generating T:G mismatches and the CpG>TpG transitions typical of ageing and cancer. Using an APOBEC1 deaminase fused to catalytically dead Cas9, the authors induce targeted, replication-independent deamination and track its repair in human cells. They show that MBD4, the primary base excision repair glycosylase for this lesion, acts in concert with a non-canonical mismatch repair branch involving MutLβ (MLH1-PMS1) and MutSα (MSH2-MSH6), demonstrate a physical interaction between MBD4 and MutLβ, and establish that repair requires MLH1. PMS1 deficiency phenocopies the CpG>TpG hypermutation signature of MBD4 loss, assigning a distinct function to PMS1; consistently, the CpG>TpG mutational burden of mismatch repair-deficient tumours is partly explained by replication-independent processes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

PMS1 is the mismatch repair gene nobody quite knows what to do with in cancer genetics: not accepted as a predisposition gene, yet present on panels and generating awkward variants of uncertain significance. This work finally gives it a measurable cellular function and its own mutational signature, providing experimental leverage for interpreting such variants — but it is in no way a demonstration of tumour risk in carriers and should not change current reporting. The laboratory take-home is rather the methodological caveat: part of the CpG>TpG burden in deficient tumours is replication-independent, which bears on interpreting signatures used as functional evidence.

Analysis by Dr Thibaut Benquey