GSE25924   Details

GSE Accession GSE25924
Title The fragile X mental retardation gene product FMRP binds methylated lysine 79 of histone H3 and plays a critical role in the DNA damage response
Submission Date 12/8/10
Last Update Date 12/1/13
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Experiment Type Genome binding/occupancy profiling by high throughput sequencing
Contributor Bing,,Ren; Yang Shi; Stephen,T,Warren; Alpatov Roman; Zhao Keiji; Chepelev Iouri
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Summary Posttranslational modifications of histones play important roles in transcription, DNA replication, and DNA damage response. In yeast, methylation of histone H3 lysine 79 (H3K79me) is recognized by the checkpoint protein Rad9 and is critical for the DNA damage response (DDR). In mammalian cells, H3K79 methylation is mediated by the methyltransferase Dot1 but proteins that recognize this modification critical for the DDR remain unknown. Here we identify the fragile X mental retardation protein, FMRP, as a novel H3K79me binding protein. In humans, loss of FMRP leads to the most common inherited form of intellectual disability, the fragile X syndrome. FMRP is predominantly present in the cytoplasm where it regulates translation of proteins important for synaptic function. However a small percentage of FMRP is localized in the nucleus where its function has remained unclear. We show that nuclear FMRP binds H3K79me through its N-terminal Agenet domain and participates in the replication stress-dependent DDR. Using FMRP mutants unable to bind H3K79me, we demonstrate by genetic complementation that the ability of FMRP to bind H3K79me is a critical determinant of the function of FMRP in the DDR. These findings uncover an unexpected role of FMRP in the DDR and suggest that FMRP-dependent maintenance of genomic stability is a potential contributing factor in the development of the fragile X syndrome.
Overall Design ChIP experiments were performed with mouse 7G1-1 anti-FMRP antibody using chromatin isolated from wild type MEFs, Dot1 mutant MEFs and FMRP KO MEFs as a control for antibody binding. 3 independent FMRP ChIP experiments were done for each cell line.
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