FAN1 通过 MLH1 的保留来控制错配修复复合物的组装，以稳定亨廷顿病中的 CAG 重复扩展。
FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.
机构信息
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.
出版信息
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。
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