The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrity
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 i...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422400035X |
| _version_ | 1797350863880060928 |
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| author | Daman Kumari Rachel Adihe Lokanga Cai McCann Thomas Ried Karen Usdin |
| author_facet | Daman Kumari Rachel Adihe Lokanga Cai McCann Thomas Ried Karen Usdin |
| author_sort | Daman Kumari |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T12:52:11Z |
| format | Article |
| id | doaj.art-398907151c9f4a538caeef7f8c4c68d4 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-08T12:52:11Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-398907151c9f4a538caeef7f8c4c68d42024-01-20T04:46:12ZengElsevieriScience2589-00422024-02-01272108814The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrityDaman Kumari0Rachel Adihe Lokanga1Cai McCann2Thomas Ried3Karen Usdin4Section 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, USASection of Cancer Genomics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USASection 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, USASection of Cancer Genomics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USASection 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S258900422400035XHuman GeneticsMolecular GeneticsEpigenetics |
| spellingShingle | Daman Kumari Rachel Adihe Lokanga Cai McCann Thomas Ried Karen Usdin The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrity iScience Human Genetics Molecular Genetics Epigenetics |
| title | The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrity |
| title_full | The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrity |
| title_fullStr | The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrity |
| title_full_unstemmed | The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrity |
| title_short | The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrity |
| title_sort | fragile x locus is prone to spontaneous dna damage that is preferentially repaired by nonhomologous end joining to preserve genome integrity |
| topic | Human Genetics Molecular Genetics Epigenetics |
| url | http://www.sciencedirect.com/science/article/pii/S258900422400035X |
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