The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrity
Daman Kumari,
Rachel Adihe Lokanga,
Cai McCann,
Thomas Ried,
Karen Usdin
Affiliations
Daman Kumari
Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Rachel Adihe Lokanga
Section of Cancer Genomics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Cai McCann
Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Thomas Ried
Section of Cancer Genomics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Karen Usdin
Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Summary: A long CGG-repeat tract in the FMR1 gene induces the epigenetic silencing that causes fragile X syndrome (FXS). Epigenetic changes include H4K20 trimethylation, a heterochromatic modification frequently implicated in transcriptional silencing. Here, we report that treatment with A-196, an inhibitor of SUV420H1/H2, the enzymes responsible for H4K20 di-/trimethylation, does not affect FMR1 transcription, but does result in increased chromosomal duplications. Increased duplications were also seen in FXS cells treated with SCR7, an inhibitor of Lig4, a ligase essential for NHEJ. Our study suggests that the fragile X (FX) locus is prone to spontaneous DNA damage that is normally repaired by NHEJ. We suggest that heterochromatinization of the FX allele may be triggered, at least in part, in response to this DNA damage.
