A Subset of the Histone H3 Lysine 9 Methyltransferases Suv39h1, G9a, GLP, and SETDB1 Participate in a Multimeric Complex

Fritsch, Lauriane; Robin, Philippe; Mathieu, Jacques; Souidi, Mouloud; Hinaux, Hélène; Rougeulle, Claire; Harel‐Bellan, Annick; Ameyar-Zazoua, Maya; Ait‐Si‐Ali, Slimane

doi:10.1016/j.molcel.2009.12.017

Cited by 280 publications

(310 citation statements)

References 56 publications

(89 reference statements)

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“…However, suv39h1 can interact with kap-1/HP1 repressor complexes (20,21,24), suggesting that kap-1 and HP1 may recruit suv39h1 to DSBs. Initially, we confirmed that kap-1 interacts with the HP1α, HP1β, and suv39h1 and that this interaction was not altered by DNA damage (Fig.…”

Section: Resultsmentioning

confidence: 99%

DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin

Ayrapetov

Gürsoy-Yüzügüllü

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

309

330

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Dynamic changes in histone modification are critical for regulating DNA double-strand break (DSB) repair. Activation of the Tip60 acetyltransferase by DSBs requires interaction of Tip60 with histone H3 methylated on lysine 9 (H3K9me3). However, how H3K9 methylation is regulated during DSB repair is not known. Here, we demonstrate that a complex containing kap-1, HP1, and the H3K9 methyltransferase suv39h1 is rapidly loaded onto the chromatin at DSBs. Suv39h1 methylates H3K9, facilitating loading of additional kap-1/HP1/suv39h1 through binding of HP1's chromodomain to the nascent H3K9me3. This process initiates cycles of kap-1/HP1/ suv39h1 loading and H3K9 methylation that facilitate spreading of H3K9me3 and kap-1/HP1/suv39h1 complexes for tens of kilobases away from the DSB. These domains of H3K9me3 function to activate the Tip60 acetyltransferase, allowing Tip60 to acetylate both ataxia telangiectasia-mutated (ATM) kinase and histone H4. Consequently, cells lacking suv39h1 display defective activation of Tip60 and ATM, decreased DSB repair, and increased radiosensitivity. Importantly, activated ATM rapidly phosphorylates kap-1, leading to release of the repressive kap-1/HP1/suv39h1 complex from the chromatin. ATM activation therefore functions as a negative feedback loop to remove repressive suv39h1 complexes at DSBs, which may limit DSB repair. Recruitment of kap-1/HP1/suv39h1 to DSBs therefore provides a mechanism for transiently increasing the levels of H3K9me3 in open chromatin domains that lack H3K9me3 and thereby promoting efficient activation of Tip60 and ATM in these regions. Further, transient formation of repressive chromatin may be critical for stabilizing the damaged chromatin and for remodeling the chromatin to create an efficient template for the DNA repair machinery.histone methylation | homologous recombination D NA double-strand breaks (DSBs) are toxic and must be repaired to maintain genomic stability. Detection of DSBs requires recruitment of the mre11-rad50-nbs1 (MRN) complex to the DNA ends (1). MRN then recruits and activates the ataxia telangiectasia-mutated (ATM) kinase (2, 3) through a mechanism that also requires the Tip60 acetyltransferase (3). Tip60 directly acetylates and activates ATM's kinase activity (4-6) and functions, in combination with MRN, to promote ATM-dependent phosphorylation of DSB repair proteins (3), including histone H2AX. This process creates domains of phosphorylated H2AX (γH2AX) extending for hundreds of kilobases along the chromatin (7,8). Mdc1 then binds to γH2AX, providing a landing pad for other DSB repair proteins, including the RNF8/RNF168 ubiquitin ligases (1, 3, 9, 10). Tip60 also plays a critical role in regulating chromatin structure at DSBs as part of the NuA4-Tip60 complex (11). NuA4-Tip60 catalyzes histone exchange (via the p400 ATPase subunit) and acetylation of histone H4 (by Tip60) at DSBs (12-15), leading to the formation of open, flexible chromatin domains adjacent to the break (12, 13). These open chromatin structures then facilitate histone ub...

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Section: Resultsmentioning

confidence: 99%

DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin

Ayrapetov

Gürsoy-Yüzügüllü

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

309

330

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“…Interestingly, LP strongly upregulated the gene expression of two chromatin modifying enzymes: EHMT2, a histonelysine N-methyltransferase, and PHF8, a histone demethylase, which were shown to act on histone 3 (Fortschegger et al 2010;Fritsch et al 2010). Upregulation of EHMT2 could be observed after treatment with all three strains compared to Inflamed tissue.…”

Section: Discussionmentioning

confidence: 96%

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

et al. 2012

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Significant health benefits have been demonstrated for certain probiotic strains through intervention studies; however, there is a shortage of experimental evidence relative to the mechanisms of action. Here, noninvasive experimental procedure based on a colon organ culture system has been used that, in contrast to most experimental in vitro models reported, can preserve natural immunohistochemical features of the human mucosa. This system has been used to test whether commensal lactobacilli (Lactobacillus paracasei BL23, Lactobacillus plantarum 299v and L. plantarum 299v (A -)) were able to hinder inflammation-like signals induced by phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO). Whole genome microarrays have been applied to analyze expression differences, from which mRNA markers could be inferred to monitor the effect of putative probiotic strains under such conditions. Regarding the gene expression, PMA/IO treatment induced not only interleukin (IL)-2 and interferon gamma (IFN-c), as expected, but also other relevant genes related to immune response and inflammation, such as IL-17A, chemokine (C-X-C motif) ligand (CXCL) 9 and CXCL11. The ex vivo culturing did not modify the pattern of expression of those genes or others related to inflammation. Interestingly, this study demonstrated that lactobacilli downregulated those genes and triggered a global change of the transcriptional profile that indicated a clear homeostasis restoring effect and a decrease in signals produced by activated T cells.

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“…There have been recent reports suggesting a requirement of Ehmt2 for genome integrity. 81,89 How a loss of Ehmt2 dependant methylation leads to chromosome instability is still not well understood; One intriguing possibility is suggested in the recent report that Ehmt2 participates in a multi-HMT complex that is required for maintaining pericentromeric chromatin, [90][91][92] a structure that is essential for proper spindle attachment and chromosome segregation during mitosis (reviewed in ref. 93).…”

Section: Emerging Roles Of Ehmt2mentioning

confidence: 99%

“…Without Ehmt2, the multi-HMT complex is disrupted leading to a drastic reduction of H3 methylation in the pericentromeric regions. 90 Additionally, there is evidence that Ehmt2 loss also perturbs centrosome number and function. EHMT2 knockdown resulted in disruptions in centrosome biogenesis leading to increased genome instability in several cancer cell lines.…”

Section: Emerging Roles Of Ehmt2mentioning

confidence: 99%

The expanding role of the Ehmt2/G9a complex in neurodevelopment

2017

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Epigenetic regulators play a crucial role in neurodevelopment. One such epigenetic complex, Ehmt1/2 (G9a/GLP), is essential for repressing gene transcription by methylating H3K9 in a highly tissue-and temporal-specific manner. Recently, data has emerged suggesting that this complex plays additional roles in regulating the activity of numerous other non-histone proteins. While much is known about the downstream effects of Ehmt1/2 function, evidence is only beginning to come to light suggesting the control of Ehmt1/2 function may be, at least in part, due to context-dependent binding partners. Here we review emerging roles for the Ehmt1/2 complex suggesting that it may play a much larger role than previously recognized, and discuss binding partners that we and others have recently characterized which act to coordinate its activity during early neurodevelopment.

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A Subset of the Histone H3 Lysine 9 Methyltransferases Suv39h1, G9a, GLP, and SETDB1 Participate in a Multimeric Complex

Cited by 280 publications

References 56 publications

DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin

DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

The expanding role of the Ehmt2/G9a complex in neurodevelopment

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