Mrg15 null and heterozygous mouse embryonic fibroblasts exhibit DNA-repair defects post exposure to gamma ionizing radiation

Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 15535 Lambda Drive, STCBM #3.100, San Antonio, TX 78245, USA.
FEBS Letters (Impact Factor: 3.17). 12/2007; 581(27):5275-81. DOI: 10.1016/j.febslet.2007.10.017
Source: PubMed


MORF4-related gene on chromosome 15 (MRG15) is a core component of the NuA4/Tip60 histone acetyltransferase complex that modifies chromatin structure. We here demonstrate that Mrg15 null and heterozygous mouse embryonic fibroblasts exhibit an impaired DNA-damage response post gamma irradiation, when compared to wild-type cells. Defects in DNA-repair and cell growth, and delayed recruitment of repair proteins to sites of damage were observed. Formation of phosphorylated H2AX and 53BP1 foci was delayed in Mrg15 mutant versus wild-type cells following irradiation. These data implicate a novel role for MRG15 in DNA-damage repair in mammalian cells.

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Available from: Kaoru Tominaga, Sep 30, 2015
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    • "Tip60 promotes the acetylationdependent ubiquitination of H2AX by UBC13, causing H2AX release from chromatin and thereby facilitates chromatin reorganization following DNA damage. We have also shown that acetylation of histone H2A, in response to ionizing radiation (IR), is impaired and recruitment of DNA repair proteins delayed in Mrg15 null MEFs (Garcia et al., 2007). Because the Tip60 complex is important for self-renewal of embryonic stem (ES) cells (Fazzio et al., 2008a, 2008b), the role of MRG15 in proliferation defects of NSC may also occur via the Tip60 complex. "
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    ABSTRACT: Chromatin regulation is crucial for many biological processes such as transcriptional regulation, DNA replication, and DNA damage repair. We have found that it is also important for neural stem/progenitor cell (NSC) function and neurogenesis. Here, we demonstrate that expression of the cyclin-dependent kinase inhibitor p21 is specifically up-regulated in Mrg15 deficient NSCs. Knockdown of p21 expression by p21 shRNA results in restoration of cell proliferation. This indicates that p21 is directly involved in the growth defects observed in Mrg15 deficient NSCs. Activated p53 accumulates in Mrg15 deficient NSCs and this most likely accounts for the up-regulation of p21 expression in the cells. We observed decreased p53 and p21 levels and a concomitant increase in the percentage of BrdU positive cells in Mrg15 null cultures following expression of p53 shRNA. DNA damage foci, as indicated by immunostaining for γH2AX and 53BP1, are detectable in a sub-population of Mrg15 deficient NSC cultures under normal growing conditions and the majority of p21-positive cells are also positive for 53BP1 foci. Furthermore, Mrg15 deficient NSCs exhibit severe defects in DNA damage response following ionizing radiation. Our observations highlight the importance of chromatin regulation and DNA damage response in NSC function and maintenance.
    Stem Cell Research 07/2011; 7(1):75-88. DOI:10.1016/j.scr.2011.04.002 · 3.69 Impact Factor
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    • "Of note, MRG15 is shared with at least two other complexes: the Tip60 (NuA4)-HAT complex [26–28] and the BRCA2-containing DNA-damage-responsive complexes [29, 30]. Although we will not discuss these complexes further in this paper, the MRG15-associated complexes are implicated in DNA-damage responses [29, 31–33], in addition to transcriptional regulation, suggesting that histone acetylation dynamics is tightly coupled with histone eviction/deposition during DNA-repair processes. "
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    ABSTRACT: Epigenetic gene silencing is one of the fundamental mechanisms for ensuring proper gene expression patterns during cellular differentiation and development. Histone deacetylases (HDACs) are evolutionally conserved enzymes that remove acetyl modifications from histones and play a central role in epigenetic gene silencing. In cells, HDAC forms a multiprotein complex (HDAC complex) in which the associated proteins are believed to help HDAC carry out its cellular functions. Though each HDAC complex contains distinct components, the presence of isoforms for some of the components expands the variety of complexes and the diversity of their cellular roles. Recent studies have also revealed a functional link between HDAC complexes and specific histone demethylases. In this paper, we summarize the distinct and cooperative roles of four class I HDAC complexes, Sin3, NuRD, CoREST, and NCoR/SMRT, with respect to their component diversity and their relationship with specific histone demethylases.
    BioMed Research International 01/2011; 2011(1110-7243):129383. DOI:10.1155/2011/129383 · 2.71 Impact Factor
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