UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK; UK Dementia Research Institute, University College London, London WC1N 3BG, UK.
UK Dementia Research Institute, University College London, London WC1N 3BG, UK; Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.
Cell Rep. 2021 Aug 31;36(9):109649. doi: 10.1016/j.celrep.2021.109649.
CAG repeat expansion in the HTT gene drives Huntington's disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, the interaction between FAN1, a DNA-structure-specific nuclease, and MLH1, member of the DNA mismatch repair pathway (MMR), is not defined. Here, we identify a highly conserved SPYF motif at the N terminus of FAN1 that binds to MLH1. Our data support a model where FAN1 has two distinct functions to stabilize CAG repeats. On one hand, it binds MLH1 to restrict its recruitment by MSH3, thus inhibiting the assembly of a functional MMR complex that would otherwise promote CAG repeat expansion. On the other hand, it promotes accurate repair via its nuclease activity. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion.
CAG 重复扩展在 HTT 基因中驱动亨廷顿病（HD）发病机制，并受 DNA 损伤修复途径调节。在这种情况下，DNA 结构特异性核酸内切酶 FAN1 与 DNA 错配修复途径（MMR）的成员 MLH1 之间的相互作用尚不清楚。在这里，我们在 FAN1 的 N 端鉴定出一个高度保守的 SPYF 基序，它与 MLH1 结合。我们的数据支持了这样一个模型，即 FAN1 具有两种截然不同的功能来稳定 CAG 重复。一方面，它结合 MLH1 以限制其被 MSH3 募集，从而抑制功能失调的 MMR 复合物的组装，否则该复合物会促进 CAG 重复扩展。另一方面，它通过其核酸酶活性促进精确修复。这些数据为减少体细胞扩展的 HD 治疗提供了一个潜在途径。
