Prime editing enables high-throughput identification and characterization of selective MutSβ inhibitors
- 1Princeton University
Abstract
DNA mismatch repair (MMR) maintains genome stability but paradoxically drives expansion of pathogenic repeats responsible for trinucleotide repeat disorders. Attenuating repeat instability through targeted inhibition of MMR is therefore a therapeutic strategy of interest; however, progress is constrained by a lack of robust methods for defining and isolating MMR subpathways. We exploited features of prime editing to profile the effects of core MMR genes on thousands of programmed DNA mispairs in cells and resolved distinct MMR processes, including a noncanonical, loop-directed mechanism. Guided by these results, we built a set of scalable reporters that detect loss of separable MMR processes and screened ~72,000 small molecules for activity against MutS{beta}-directed MMR. This effort identified a novel series of MutS{beta} inhibitors that reduced (CAG)n expansion in a cell model. Altogether, this study establishes several methods for systematically interrogating MMR, with demonstrated capacity to identify inhibitors of therapeutic value.
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BibTeX
@misc{jing2026prime,
title = {{Prime editing enables high-throughput identification and characterization of selective MutSβ inhibitors}},
author = {Y. Jing and J. Yan and D. Yang and Y. Chen and I. Senoussi and J. Woodward and K. Williams and H. Kim and K. He and H. Daub and V. Dahiya and M. Thomsen and J. Ling and P. Ravisankar and Y. Pritykin and G. Balmus and P. Cejka and J. A. Hussmann and L. Liu and T. F. Vogt and M. Finley and B. Adamson},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.755959},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.755959v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Prime editing enables high-throughput identification and characterization of selective MutSβ inhibitors
AU - Y. Jing
AU - J. Yan
AU - D. Yang
AU - Y. Chen
AU - I. Senoussi
AU - J. Woodward
AU - K. Williams
AU - H. Kim
AU - K. He
AU - H. Daub
AU - V. Dahiya
AU - M. Thomsen
AU - J. Ling
AU - P. Ravisankar
AU - Y. Pritykin
AU - G. Balmus
AU - P. Cejka
AU - J. A. Hussmann
AU - L. Liu
AU - T. F. Vogt
AU - M. Finley
AU - B. Adamson
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.755959
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.755959v1
AB - DNA mismatch repair (MMR) maintains genome stability but paradoxically drives expansion of pathogenic repeats responsible for trinucleotide repeat disorders. Attenuating repeat instability through targeted inhibition of MMR is therefore a therapeutic strategy of interest; however, progress is constrained by a lack of robust methods for defining and isolating MMR subpathways. We exploited features of prime editing to profile the effects of core MMR genes on thousands of programmed DNA mispairs in cells and resolved distinct MMR processes, including a noncanonical, loop-directed mechanism. Guided by these results, we built a set of scalable reporters that detect loss of separable MMR processes and screened ~72,000 small molecules for activity against MutS{beta}-directed MMR. This effort identified a novel series of MutS{beta} inhibitors that reduced (CAG)n expansion in a cell model. Altogether, this study establishes several methods for systematically interrogating MMR, with demonstrated capacity to identify inhibitors of therapeutic value.
ER -