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Regulation of the DNA Damage Response and Gene Expression by the Dot1L Histone Methyltransferase and the 53Bp1 Tumour Suppressor

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dc.contributor.author FitzGerald, Jennifer en
dc.contributor.author Moureau, Sylvie en
dc.contributor.author O'Connell, Enda en
dc.contributor.author Grenon, Muriel en
dc.contributor.author Muriel, Noel F. en
dc.date.accessioned 2011-05-25T12:22:51Z en
dc.date.available 2011-05-25T12:22:51Z en
dc.date.issued 2011-02 en
dc.identifier.citation FitzGerald, J., Moureau, S., Drogaris, P., O'Connell, E., Abshiru, N., Verreault, A., et al. (2011) Regulation of the DNA Damage Response and Gene Expression by the Dot1L Histone Methyltransferase and the 53Bp1 Tumour Suppressor. PLoS ONE, 6(2), e14714. en
dc.identifier.uri http://hdl.handle.net/10379/1936 en
dc.description.abstract Background Dot1L, a histone methyltransferase that targets histone H3 lysine 79 (H3K79), has been implicated in gene regulation and the DNA damage response although its functions in these processes remain poorly defined. Methodology/Principal Findings Using the chicken DT40 model system, we generated cells in which the Dot1L gene is disrupted to examine the function and focal recruitment of the 53Bp1 DNA damage response protein. Detailed kinetic and dose response assays demonstrate that, despite the absence of H3K79 methylation demonstrated by mass spectrometry, 53Bp1 focal recruitment is not compromised in these cells. We also describe, for the first time, the phenotypes of a cell line lacking both Dot1L and 53Bp1. Dot1L¿/¿ and wild type cells are equally resistant to ionising radiation, whereas 53Bp1¿/¿/Dot1L¿/¿ cells display a striking DNA damage resistance phenotype. Dot1L and 53Bp1 also affect the expression of many genes. Loss of Dot1L activity dramatically alters the mRNA levels of over 1200 genes involved in diverse biological functions. These results, combined with the previously reported list of differentially expressed genes in mouse ES cells knocked down for Dot1L, demonstrates surprising cell type and species conservation of Dot1L-dependent gene expression. In 53Bp1¿/¿ cells, over 300 genes, many with functions in immune responses and apoptosis, were differentially expressed. To date, this is the first global analysis of gene expression in a 53Bp1-deficient cell line. Conclusions/Significance Taken together, our results uncover a negative role for Dot1L and H3K79 methylation in the DNA damage response in the absence of 53Bp1. They also enlighten the roles of Dot1L and 53Bp1 in gene expression and the control of DNA double-strand repair pathways in the context of chromatin. en
dc.format application/pdf en
dc.language.iso en en
dc.publisher PLoS en
dc.subject Methylation en
dc.subject School of Natural Science en
dc.subject NCBES en
dc.title Regulation of the DNA Damage Response and Gene Expression by the Dot1L Histone Methyltransferase and the 53Bp1 Tumour Suppressor en
dc.type Article en
dc.local.publishedsource http://dx.crossref.org/10.1371%2Fjournal.pone.0014714 en
dc.description.peer-reviewed peer-reviewed en
dc.contributor.funder IRSET en
dc.contributor.funder FP6 en
dc.contributor.funder SFI en

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