The Mammalian Ortholog of <i>Drosophila</i> MOF That Acetylates Histone H4 Lysine 16 Is Essential for Embryogenesis and Oncogenesis

Gupta, A.; Guerin-Peyrou, T. Geraldine; Sharma, Girdhar G.; Park, Changwon; Agarwal, Manjula; Ganju, Ramesh K.; Pandita, Shruti; Choi, Kyunghee; Sukumar, Saraswati; Pandita, Raj K.; Ludwig, Thomas; Pandita, Tej K.

doi:10.1128/mcb.01045-07

Cited by 198 publications

(266 citation statements)

References 50 publications

(81 reference statements)

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“…H4K16 acetylation in higher eukaryotes is mainly carried out by MOF histone acetyltransferase [17][18][19][20]. We speculated whether H4K16ac downregulation could be a consequence of the decreasing MOF protein levels following aberrant activation of the Notch pathway.…”

Section: Notch-induced Downregulation Of Mof Through Mdm2mentioning

confidence: 99%

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

et al. 2014

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Identification of the epigenetic mechanisms involved in the transmission of Notch signaling is useful for personalized medicine. We observed that aberrantly high levels of Notch activity resulted in H4K16ac downregulation in hepatocellular carcinoma and breast cancer cell lines and tissues. This downregulated acetylation was a consequence of increased male on the first degradation following the upregulation of full‐length murine double minute 2 in different cancer types. We observed that increases in male on the first could attenuate heterogeneity induced by aberrantly high levels of Notch activity. Our results provide new insights into the analysis and treatment of Notch‐induced hepatocellular carcinoma and breast cancer.

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Section: Notch-induced Downregulation Of Mof Through Mdm2mentioning

confidence: 99%

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

et al. 2014

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“…chromosome of Drosophila are associated with robust H4-Lys16 acetylation (22). Our recent studies have revealed that MOF inactivation or depletion in mammalian cells results in loss of H4K16ac, which correlates with loss of cellular proliferation (24). Since several studies have suggested that lack of DDR components is likely to be responsible for loss of cellular proliferation and that IR-induced DNA damage status correlates with cell survival, we determined whether depletion of hMOF downregulates any specific gene(s) involved in the mammalian DDR.…”

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confidence: 99%

“…The histone acetyltransferase (HAT) responsible for the majority of H4K16 acetylation in the cell is MOF (2,24,25,46,75,79). A single histone H4K16ac modification modulates both higher-order chromatin structure and functional interactions between a nonhistone protein and the chromatin fiber (74).…”

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confidence: 99%

“…The remaining pellets are fraction IV, which were finally lysed in SDS-PAGE buffer and boiled for 5 min. From each fraction, equal aliquots derived from equivalent cell numbers were loaded on 10% SDS-PAGE gels and blotted as previously described (24,25,69,71). chromosome of Drosophila are associated with robust H4-Lys16 acetylation (22).…”

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confidence: 99%

“…After air drying, slides were stored at Ϫ20°C until further use. Immunofluorescent staining was done as described previously (24,67).…”

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MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair

Sharma

Gupta

et al. 2010

Molecular and Cellular Biology

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The human MOF gene encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac). Here we show that reduced levels of H4K16ac correlate with a defective DNA damage response (DDR) and double-strand break (DSB) repair to ionizing radiation (IR). The defect, however, is not due to altered expression of proteins involved in DDR. Abrogation of IR-induced DDR by MOF depletion is inhibited by blocking H4K16ac deacetylation. MOF was found to be associated with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a protein involved in nonhomologous end-joining (NHEJ) repair. ATM-dependent IR-induced phosphorylation of DNA-PKcs was also abrogated in MOF-depleted cells. Our data indicate that MOF depletion greatly decreased DNA double-strand break repair by both NHEJ and homologous recombination (HR). In addition, MOF activity was associated with general chromatin upon DNA damage and colocalized with the synaptonemal complex in male meiocytes. We propose that MOF, through H4K16ac (histone code), has a critical role at multiple stages in the cellular DNA damage response and DSB repair.In eukaryotes, specifically in mammals, the mechanisms by which the DNA damage response (DDR) components gain access to broken DNA in compacted chromatin remain a mystery. The DNA damage response occurs within the context of chromatin, and its structure is altered post-DNA double-strand break (DSB) induction. Major alterations include (i) chromatin remodeling via ATP-dependent activities and covalent histone modifications and (ii) incorporation of histone variants into nucleosomes. Chromatin structure creates a natural barrier to damaged DNA sites, which suggests that histone modifications will play a primary role in DDR by facilitating repair protein access to DNA breaks (43,58,87,88). While some experimental evidence indicates that preexisting histone modifications may play an important role in DDR, the precise role of chromatin status prior to DNA damage on DDR is yet to be clearly established. For instance, biochemical and cell biology studies indicate that repair proteins (53BP1, Schizosaccharomyces pombe Crb2 [SpCrb2], and Saccharomyces cerevisiae Rad9 [ScRad9]) require methylated Lys79 of histone H3 (H3-K79) (29) or methylated Lys20 of histone H4 (H4-K20) and/or CBP/p300-mediated acetylation of histone H3 on lysine 56 (9,15,29,66,93) for focus formation at DNA-damaged sites. These modifications are normally present on chromatin, and none has been reported to change in response to ionizing radiation (IR)-induced DNA damage. However, it is yet to be established whether preexisting acetylation of specific histone residues at the time of cellular exposure to IR plays any critical role in DDR. While recent studies demonstrate that in human cells, histone H3 acetylated at K9 (H3K9ac) and H3K56ac are rapidly and reversibly reduced in response to DNA damage, most histone acetylation modifications do not change appreciably after genotoxic stress (80).The amino-terminal tail of histone H4 is a well-described target fo...

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Suboptimal extracellular pH values alter DNA damage response to induced double‐strand breaks

et al. 2018

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Conditions leading to unrepaired DNA double‐stranded breaks are potent inducers of genetic instability. Systemic conditions may lead to fluctuation of hydrogen ions in the cellular microenvironment, and we show that small variations in extracellular pH , termed suboptimal pH e, can decrease the efficiency of DNA repair in the absence of intracellular pH variation. Recovery from bleomycin‐induced DNA double‐stranded breaks in fibroblasts proceeded less efficiently at suboptimal pH e values ranging from 7.2 to 6.9, as shown by the persistence of repair foci, reduction of H4K16 acetylation, and chromosomal instability, while senescence or apoptosis remained undetected. By allowing escape from these protective mechanisms, suboptimal pH e may therefore enhance the genotoxicity of double‐stranded breaks, leading to genetic instability.

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The Mammalian Ortholog of Drosophila MOF That Acetylates Histone H4 Lysine 16 Is Essential for Embryogenesis and Oncogenesis

Cited by 198 publications

References 50 publications

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair

Suboptimal extracellular pH values alter DNA damage response to induced double‐strand breaks

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