FAN1's protection against CGG repeat expansion requires its nuclease activity and is FANCD2-independent

Nucleic Acids Res. 2021 Nov 18;49(20):11643-11652. doi: 10.1093/nar/gkab899.


The Repeat Expansion Diseases, a large group of human diseases that includes the fragile X-related disorders (FXDs) and Huntington's disease (HD), all result from expansion of a disease-specific microsatellite via a mechanism that is not fully understood. We have previously shown that mismatch repair (MMR) proteins are required for expansion in a mouse model of the FXDs, but that the FANCD2 and FANCI associated nuclease 1 (FAN1), a component of the Fanconi anemia (FA) DNA repair pathway, is protective. FAN1's nuclease activity has been reported to be dispensable for protection against expansion in an HD cell model. However, we show here that in a FXD mouse model a point mutation in the nuclease domain of FAN1 has the same effect on expansion as a null mutation. Furthermore, we show that FAN1 and another nuclease, EXO1, have an additive effect in protecting against MSH3-dependent expansions. Lastly, we show that the loss of FANCD2, a vital component of the Fanconi anemia DNA repair pathway, has no effect on expansions. Thus, FAN1 protects against MSH3-dependent expansions without diverting the expansion intermediates into the canonical FA pathway and this protection depends on FAN1 having an intact nuclease domain.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Catalytic Domain*
  • DNA Repair Enzymes / metabolism
  • Endodeoxyribonucleases / chemistry
  • Endodeoxyribonucleases / genetics
  • Endodeoxyribonucleases / metabolism*
  • Exodeoxyribonucleases / chemistry
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism*
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Fanconi Anemia Complementation Group D2 Protein / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Multifunctional Enzymes / chemistry
  • Multifunctional Enzymes / genetics
  • Multifunctional Enzymes / metabolism*
  • MutS Homolog 3 Protein / metabolism
  • Point Mutation
  • Trinucleotide Repeat Expansion*


  • Fancd2 protein, mouse
  • Fanconi Anemia Complementation Group D2 Protein
  • Msh3 protein, mouse
  • Multifunctional Enzymes
  • MutS Homolog 3 Protein
  • Endodeoxyribonucleases
  • Exo1 protein, mouse
  • Exodeoxyribonucleases
  • Fan1 protein, mouse
  • DNA Repair Enzymes