FAN1, short for FANCD2/FANCI-associated nuclease, encodes a DNA repair nuclease. It is involved in DNA interstrand cross-link repair and is associated with pathways related to maintaining chromosomal stability. Genetic variations in FAN1 have been linked to various diseases, such as karyomegalic interstitial nephritis, 15q13.3 microdeletion/microduplication syndrome (associated with autism, schizophrenia, and epilepsy), cancer, and repeat expansion diseases [1].

In HD and FMR1 transgenic mice, Fan1 is required to suppress high levels of ongoing somatic CAG and CGG repeat expansions respectively [1]. In human cell extracts, FAN1 can remove triplet repeat extrusions via a PCNA-and RFC-dependent mechanism, preventing repeat expansion [2]. FAN1 also controls mismatch repair complex assembly by binding to MLH1, thus stabilizing CAG repeat expansion in HD [3]. Disruption of the FAN1-MLH1 interaction leads to cellular hypersensitivity to ICL damage and defective repair of CAG/CTG slip-outs [4].

In conclusion, FAN1 plays a crucial role in DNA repair, especially in preventing repeat expansions. Studies using transgenic mouse models have revealed its significance in diseases like Huntington's disease. Understanding FAN1's functions may offer potential therapeutic targets for treating related diseases.

References:

1. Deshmukh, Amit L, Porro, Antonio, Mohiuddin, Mohiuddin, Sartori, Alessandro A, Pearson, Christopher E. . FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders. In Journal of Huntington's disease, 10, 95-122. doi:10.3233/JHD-200448. https://pubmed.ncbi.nlm.nih.gov/33579867/

2. Phadte, Ashutosh S, Bhatia, Mayuri, Ebert, Hope, Komolov, Konstantin E, Pluciennik, Anna. 2023. FAN1 removes triplet repeat extrusions via a PCNA- and RFC-dependent mechanism. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2302103120. doi:10.1073/pnas.2302103120. https://pubmed.ncbi.nlm.nih.gov/37549289/

3. Goold, Robert, Hamilton, Joseph, Menneteau, Thomas, Balmus, Gabriel, Tabrizi, Sarah J. . FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease. In Cell reports, 36, 109649. doi:10.1016/j.celrep.2021.109649. https://pubmed.ncbi.nlm.nih.gov/34469738/

4. Porro, Antonio, Mohiuddin, Mohiuddin, Zurfluh, Christina, Pearson, Christopher E, Sartori, Alessandro A. 2021. FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG/CTG repeats. In Science advances, 7, . doi:10.1126/sciadv.abf7906. https://pubmed.ncbi.nlm.nih.gov/34330701/