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Comment
. 2023 Jun 7;31(6):1509-1511.
doi: 10.1016/j.ymthe.2023.05.010. Epub 2023 May 25.

Can MSH3 lowering stop HTT repeat expansion in its CAG tract?

Ross Ferguson  1 , Sarah J Tabrizi  2
Affiliations
Comment

Can MSH3 lowering stop HTT repeat expansion in its CAG tract?

Ross Ferguson et al. Mol Ther. .
No abstract available

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Conflict of interest statement

Declaration of interests In the past year, through the offices of UCL Consultants Ltd, a wholly owned subsidiary of University College London, S.J.T. has undertaken consultancy services for Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffman-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis Pharma, Pfizer, Prilenia Neurotherapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, UniQure Biopharma, and Vertex Pharmaceuticals. In the past 12 months, University College London Hospitals NHS Foundation Trust, S.J.T.’s host clinical institution, received funding to run clinical trials for F. Hoffman-La Roche, Novartis Pharma, PTC Therapeutics, and UniQure Biopharma.

Figures

Figure 1
Figure 1
Mismatch repair and its role in repeat expansions (A) Mismatch repair is initiated by detection of mispairing by two heterodimeric MutS complexes. MutSα (MSH2 and MSH6) recognizes single base mismatches and 1- to 4-bp loop-outs, while the MutSβ complex (MSH2 and MSH3) detects small 2- to 10-bp DNA extrusions. Detection results in the recruitment of MutL family heterodimers to form a ternary complex. The endonuclease activity of MutL factor PMS2 nicks the DNA in the strand harboring the incorrect sequence. This allows loading of Exo1, which excises nucleotides 5′ to 3′ until it reaches a flanking nick. The resulting gap is then filled by DNA polymerase delta and nicks ligated closed by LIG1. (B) CAG loop-out structures form at the expanded repeat in exon 1 of the huntingtin gene during replication and transcription. These loop-outs are detected by MutSβ (MSH2 and MSH3), which then recruits MutL heterodimers such as MutLα (MLH1 and PMS2). The strand opposing the loop-out is nicked (asterisk) and resected. The additional bases comprising the loop-out are incorporated into the opposing strand during synthesis and ligation, increasing the length of the repeat. Where MSH3 is absent due to knockout or reduced due to divalent-siRNAs, this process cannot occur. The loop-outs are resolved through other means maintaining the pre-existing length of the CAG repeat.
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References

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