Published in Nature Communications, the work from the Cejka laboratory reveals how MutSβ-MutLγ-driven trinucleotide expansion arise in neural cells and how FAN1 safeguards the genome. This mechanism clarifies Huntington’s disease biology and points to therapeutic targets.
Huntington’s disease is driven by the gradual expansion of CAG repeats in the HTT gene in brain cells. How this expansion occurs has remained unclear. The latest study from the Cejka laboratory shows that the MutLγ nuclease makes DNA incisions that trigger repeat expansion, while another nuclease, FAN1, protects the DNA by counteracting these pathological cuts. This study provides, for the first time, a concrete mechanistic answer to the question: how does expansion happen? Understanding these fundamentals opens the door to “what next”. If we understand the pathways that trigger the expansion or prevent it, we may be able to target the key factors to slow or limit repeat growth and, ultimately, change the course of the disease. The new findings give researchers solid starting points for future treatment strategies and help connect decades of genetic observations to a mechanism that explain the disease’s origin at the cellular level.
This works was primarily carried out by Ph.D student Issam Senoussi, with the help of Dr. Valentina Mengoli and in collaboration with Dr. Andrés Marco, bioinformatician at Data Curators and Arianna Cerana, Dr. Andrea Rinaldi and Simone G. Moro from the genomic facility at the Institute for Research in Biomedicine, affiliated with the Università della Svizzera italiana.
Mechanism of trinucleotide repeat expansion by MutSβ-MutLγ and contraction by FAN1
Senoussi, I., Mengoli, V., Cerana, A. et al. Mechanism of trinucleotide repeat expansion by MutSβ-MutLγ and contraction by FAN1. Nat Commun 16, 9445 (2025).
