Journal
DNA REPAIR
Volume 74, Issue -, Pages 63-69Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.dnarep.2018.12.004
Keywords
Fragile X related disorders; Fragile X syndrome (FXS); Repeat Expansion Diseases; Double-strand break repair (DSBR); Non-homologous end-joining (NHEJ); DNA ligase IV (Lig4); MRE11
Categories
Funding
- Intramural Program of the NIDDK [DK057808]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK057808] Funding Source: NIH RePORTER
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Expansion of a CGG-repeat tract in the 5' UTR of FMR1 is responsible for the Fragile X-related disorders (FXDs), FXTAS, FXPOI and FXS. Previous work in a mouse model of these disorders has implicated proteins in the base excision and the mismatch repair (MMR) pathways in the expansion mechanism. However, the precise role of these factors in this process is not well understood. The essential role of MutL gamma, a complex that plays a minor role in MMR but that is essential for resolving Holliday junctions during meiosis, raises the possibility that expansions proceed via a Holliday junction-like intermediate that is processed to generate a double-strand break (DSB). We show here in an FXD mouse model that LIG4, a ligase essential for non-homologous end-joining (NHEJ), a form of DSB repair (DSBR), protects against expansions. However, a mutation in MRE11, a nuclease that is important for several other DSBR pathways including homologous recombination (HR), has no effect on the extent of expansion. Our results suggest that the expansion pathway competes with NHEJ for the processing of a DSB intermediate. Thus, expansion likely proceeds via an NHEJ-independent DSBR pathway that may also be HR-independent.
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