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MISMATCH REPAIR

Tandem regulation of MutS activity by ATP and DNA during MMR initiation

Nature Structural & Molecular Biology volume 29, pages 5–7 (2022)Cite this article

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An elegant cryo-EM and biophysical study unveils the conformational changes of the E. coli MutS mismatch repair factor. This provides a nice follow-up to the recent report from the same group characterizing how MutS scans DNA without initiating repair on correctly base-paired DNA and recruits MutL upon encountering a mismatch.

The mismatch repair (MMR) pathway is a powerful, evolutionarily conserved mutation-avoidance mechanism that corrects base–base mismatches and insertion/deletion loops arising during DNA replication1. It increases the fidelity of DNA synthesis 100- to 1,000-fold. Inactivation of MMR in human causes genetic instability that has been associated with the development of hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), as well as a fraction of sporadic tumors in a number of tissues. In Escherichia coli, the MMR pathway involves the recognition by the MutS homodimer of a mismatched DNA base pair. Upon binding to the mismatch, MutS kinks the DNA at the mismatch position by 60°2,3. The MutS homodimer functions as an heterodimer, with the two subunits playing asymmetric roles. One subunit interacts with the mismatch and inserts a conserved phenylalanine into the DNA adjacent to the mismatched base. The homodimer then undergoes an ATP-dependent conformational change and forms a sliding clamp conformation. MutS can then slide along the DNA and recruit the MutL homodimer. The MutS–MutL complex activates the MutH endonuclease, which can incise the nascent strand at hemimethylated GATC sequence. The nascent strand is then degraded by 5′-3′ and 3′-5′ exonucleases with the help of a helicase, UvrD, while the new strand is resynthesized by a polymerase and sealed by a DNA ligase. In most bacteria beside a small subset of gamma-proteobacteria that includes E. coli, there are some variations in this process, as no MutH nuclease is present and MutL has an endonuclease activity that is directed to the nascent strand by the β-clamp. In eukaryotes, the MMR is initiated by MutS and MutL homologs that are heterodimers. The MutL homologs present an endonuclease site on one subunit of the heterodimer and are directed to the nascent strand by the PCNA processive factor.

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Fig. 1: Borsellini et al. report four cryo-EM structures of MutS in its apo form (grey) with ADP (orange), ATP or ATP analog (red) nucleotides.

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Acknowledgements

J.B.C. thanks the French National Research Agency for support (ANR-20-CE11-0026, ANR-17-CE12-0020 and ANR- 18-CE44-0008).

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  1. Institute for Integrative Biology of the Cell (I2BC), Université Paris–Saclay, CEA, CNRS, Gif-sur-Yvette, France

    Jean Baptiste Charbonnier

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Correspondence to Jean Baptiste Charbonnier.

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Charbonnier, J.B. Tandem regulation of MutS activity by ATP and DNA during MMR initiation. Nat Struct Mol Biol 29, 5–7 (2022). https://doi.org/10.1038/s41594-021-00713-3

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