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

Anaïs Le Ven1,2, Sandra Vanhuele1, Olivier Ganier1

  • 1Inserm U1339 UMR3666, DNA Repair and Uveal Melanoma (D.R.U.M.), Institut Curie, PSL Research University, Paris 75005, France.

Nucleic Acids Research
|August 11, 2026
PubMed

Insights

DNA repair mechanisms prevent mutations from 5-methylcytosine deamination. This study reveals a novel interplay between base excision repair and mismatch repair pathways, highlighting their role in maintaining genomic integrity.

Area of Science:

  • Genetics
  • Molecular Biology
  • Genomic Stability

Background:

  • CpG dinucleotides are prone to mutations via 5-methylcytosine deamination, leading to CpG>TpG transitions, a common feature in aging and cancer.
  • MBD4 was previously identified as the main enzyme for repairing 5-methylcytosine deamination.

Purpose of the Study:

  • To investigate the repair mechanisms of targeted 5-methylcytosine deamination independently of DNA replication.
  • To elucidate the interaction between base excision repair (BER) and mismatch repair (MMR) pathways in maintaining genomic integrity.

Main Methods:

  • Utilized a fusion of APOBEC1 deaminase and catalytically dead Cas9 to induce targeted 5-methylcytosine deamination in human cells.
  • Tracked the repair process and analyzed the involvement of specific repair complexes, including MBD4, MutLβ (MLH1-PMS1), and MutSα (MSH2-MSH6).

Main Results:

  • Demonstrated that MBD4 collaborates with a non-canonical mismatch repair pathway involving MutLβ and MutSα.
  • Uncovered a physical interaction between MBD4 and MutLβ, and confirmed that MBD4-mediated repair is dependent on MLH1.
  • Showcased that PMS1 deficiency results in a hypermutation signature similar to MBD4 loss, indicating a crucial role for PMS1 in 5-methylcytosine deamination repair.

Conclusions:

  • Established 5-methylcytosine deamination repair as a key function of human PMS1.
  • Revealed a novel role for non-canonical mismatch repair in conjunction with base excision repair to protect against methylated DNA damage.
  • Suggested that replication-independent processes contribute to the CpG>TpG mutational burden observed in mismatch repair-deficient tumors.

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