Maring, Berdien (2024) Molecular Mechanisms of FAN1 in CAG Repeat Instability: Implications for HD and SCAs. Master's Thesis / Essay, Biomedical Sciences.
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Abstract
CAG repeat instability is a hallmark of Huntington's disease (HD) and spinocerebellar ataxias (SCAs), contributing to disease onset and progression through somatic expansions in affected tissues. Genome-wide association studies (GWAS) have identified FAN1 as a key genetic modifier of the age of onset in both disorders. This review synthesizes current research on FAN1's role in maintaining genomic stability, particularly through its dual nuclease activities and interaction with DNA repair pathways, such as the mismatch repair (MMR) system. This review highlights findings that FAN1 counteracts MMR-induced instability, preventing repeat expansions. We explore the molecular mechanisms by which FAN1 stabilizes CAG repeats, including its structural domains, nuclease functions, and competition with MMR proteins. Specific FAN1 variants, particularly those in 3′ UTR regions and TPR-domain, are associated with delayed disease onset and slower progression. These insights suggest therapeutic potential for targeting FAN1 in HD and SCAs, with approaches such as antisense oligonucleotides under development to enhance its protective role. Although FAN1's role in HD is well investigated, more research is needed to confirm its role in SCAs. While the mechanisms may be similar, the specific interactions and effects in SCAs require further elucidation.
| Item Type: | Thesis (Master's Thesis / Essay) |
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| Supervisor name: | Westers, H. and Diemen, C.C. van |
| Degree programme: | Biomedical Sciences |
| Thesis type: | Master's Thesis / Essay |
| Language: | English |
| Date Deposited: | 03 Dec 2024 09:25 |
| Last Modified: | 03 Dec 2024 09:25 |
| URI: | https://fse.studenttheses.ub.rug.nl/id/eprint/34469 |
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