Intersection of the fragile X-related disorders and the DNA damage response

• Published in: DNA repair Vol. 144; p. 103785
• Main Authors: Kumari, Daman, Grant-Bier, Jessalyn, Kadyrov, Farid, Usdin, Karen
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2024
• Subjects: Animals; Chromosome fragility; DNA Damage; DNA Repair; Double-strand breaks (DSBs); Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; Humans; Microsatellite instability; Mismatch repair (MMR); MutLα; Non-homologous end-joining (NHEJ); Repeat expansion diseases; Trinucleotide Repeat Expansion; Mismatch repair (MMR); Chromosome fragility; Non-homologous end-joining (NHEJ); Repeat expansion diseases; Double-strand breaks (DSBs); MutLα; Microsatellite instability
• ISSN: 1568-7864; 1568-7856; 1568-7856
• DOI: 10.1016/j.dnarep.2024.103785

The Repeat Expansion Diseases (REDs) are a large group of human genetic disorders that result from an increase in the number of repeats in a disease-specific tandem repeat or microsatellite. Emerging evidence suggests that the repeats trigger an error-prone form of DNA repair that causes the expansion mutation by exploiting a limitation in normal mismatch repair. Furthermore, while much remains to be understood about how the mutation causes pathology in different diseases in this group, there is evidence to suggest that some of the downstream consequences of repeat expansion trigger the DNA damage response in ways that contribute to disease pathology. This review will discuss these subjects in the context of the Fragile X-related disorders (aka the FMR1 disorders) that provide a particularly interesting example of the intersection between the repeats and the DNA damage response that may also be relevant for many other diseases in this group. •The Fragile X-related disorders result from misapplication of the MMR machinery.•The resultant mutation potentially affects genome integrity in multiple ways.•These include effects on DNA processing that results in chromosomal abnormalities.•It may also trigger gene silencing and the loss of a protein involved in DNA repair.•The same is likely true for many of the >45 other known Repeat Expansion Diseases.