FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders
| Autor: | Gagan B. Panigrahi, Jean-Yves Masson, Amit Laxmikant Deshmukh, Antonio Porro, Mohiuddin Mohiuddin, Stella Lanni, Christopher E. Pearson, Alessandro A. Sartori, Marie-Christine Caron |
|---|---|
| Přispěvatelé: | University of Zurich, Jones, Lesley, Pearson, Christopher E, Wheeler, Vanessa |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
DNA Repair DNA repair 2804 Cellular and Molecular Neuroscience Clinical Neurology 610 Medicine & health Review Biology Genomic Instability 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Huntington's disease FAN1 medicine Animals Humans Spinocerebellar Ataxias Copy-number variation nuclease Gene repeat instability Genetics modifier Endodeoxyribonucleases Genes Modifier 10061 Institute of Molecular Cancer Research medicine.disease Multifunctional Enzymes FMR1 karyomegalic interstitial nephritis Exodeoxyribonucleases Huntington Disease 2728 Neurology (clinical) 030104 developmental biology Spinocerebellar ataxia 570 Life sciences biology Neurology (clinical) Trinucleotide Repeat Expansion Trinucleotide repeat expansion 030217 neurology & neurosurgery Huntington’s disease |
| Zdroj: | Journal of Huntington's Disease |
| ISSN: | 1879-6400 1879-6397 |
| DOI: | 10.3233/jhd-200448 |
| Popis: | FAN1 encodes a DNA repair nuclease. Genetic deficiencies, copy number variants, and single nucleotide variants of FAN1 have been linked to karyomegalic interstitial nephritis, 15q13.3 microdeletion/microduplication syndrome (autism, schizophrenia, and epilepsy), cancer, and most recently repeat expansion diseases. For seven CAG repeat expansion diseases (Huntington’s disease (HD) and certain spinocerebellar ataxias), modification of age of onset is linked to variants of specific DNA repair proteins. FAN1 variants are the strongest modifiers. Non-coding disease-delaying FAN1 variants and coding disease-hastening variants (p.R507H and p.R377W) are known, where the former may lead to increased FAN1 levels and the latter have unknown effects upon FAN1 functions. Current thoughts are that ongoing repeat expansions in disease-vulnerable tissues, as individuals age, promote disease onset. Fan1 is required to suppress against high levels of ongoing somatic CAG and CGG repeat expansions in tissues of HD and FMR1 transgenic mice respectively, in addition to participating in DNA interstrand crosslink repair. FAN1 is also a modifier of autism, schizophrenia, and epilepsy. Coupled with the association of these diseases with repeat expansions, this suggests a common mechanism, by which FAN1 modifies repeat diseases. Yet how any of the FAN1 variants modify disease is unknown. Here, we review FAN1 variants, associated clinical effects, protein structure, and the enzyme’s attributed functional roles. We highlight how variants may alter its activities in DNA damage response and/or repeat instability. A thorough awareness of the FAN1 gene and FAN1 protein functions will reveal if and how it may be targeted for clinical benefit. |
| Databáze: | OpenAIRE |
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