| First Author | Goold R | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 9 | Pages | 109649 |
| PubMed ID | 34469738 | Mgi Jnum | J:324645 |
| Mgi Id | MGI:6765710 | Doi | 10.1016/j.celrep.2021.109649 |
| Citation | Goold R, et al. (2021) FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease. Cell Rep 36(9):109649 |
| abstractText | 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. |
