The histone demethylase LSD1/KDM1A promotes the DNA damage response

Mosammaparast, Nima; Kim, Haeyoung; Beaugerie, Laurent; Zhao, Yu; Lim, Hui Jun; Majid, Mona C.; Dango, Sebastian; Luo, Yuying; Hempel, Kristina; Sowa, Matthew E.; Gygi, Steven P.; Steen, Hanno; Yankner, Bruce A.; Shi, Yang

doi:10.1083/jcb.201302092

Cited by 116 publications

(96 citation statements)

References 70 publications

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“…In agreement with recent literature (Mosammaparast et al, 2013), we did not find the colocalisation of KDM6B with γH2AX-positive DNA damage, and we extend this observation to KDM6A. Although we cannot exclude the possibility that KDM6A and KDM6B are recruited to γH2AX-positive foci at a level below the detection limit of immunofluorescence microscopy analyses, our observations are so far consistent with an indirect role of KDM6 activity in DNA repair.…”

Section: Discussionsupporting

confidence: 80%

“…6). In conclusion, and in agreement with previous reports on UV-induced damage (Mosammaparast et al, 2013;Šustáčková et al, 2012), we did not observe colocalisation between KDM6B or KDM6A and γH2AX at sites of laser-microirradiation-induced DNA damage. These data are consistent with a differential requirement for H3K27me3 at sites of DNA damage in undifferentiated and differentiating ESCs.…”

Section: Inhibition Of Kdm6 Protein Activity During Esc Differentiatisupporting

confidence: 81%

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Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage

Hofstetter¹,

Kampka²,

Huppertz³

et al. 2016

Development

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Pluripotent embryonic stem cells (ESCs) are characterised by their capacity to self-renew indefinitely while maintaining the potential to differentiate into all cell types of an adult organism. Both the undifferentiated and differentiated states are defined by specific gene expression programs that are regulated at the chromatin level. Here, we have analysed the contribution of the H3K27me2-and H3K27me23-specific demethylases KDM6A and KDM6B to murine ESC differentiation by employing the GSK-J4 inhibitor, which is specific for KDM6 proteins, and by targeted gene knockout (KO) and knockdown. We observe that inhibition of the H3K27 demethylase activity induces DNA damage along with activation of the DNA damage response (DDR) and cell death in differentiating but not in undifferentiated ESCs. Laser microirradiation experiments revealed that the H3K27me3 mark, but not the KDM6B protein, colocalise with γH2AX-positive sites of DNA damage in differentiating ESCs. Lack of H3K27me3 attenuates the GSK-J4-induced DDR in differentiating Eed-KO ESCs. Collectively, our findings indicate that differentiating ESCs depend on KDM6 and that the H3K27me3 demethylase activity is crucially involved in DDR and survival of differentiating ESCs.

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Section: Discussionsupporting

confidence: 80%

Section: Inhibition Of Kdm6 Protein Activity During Esc Differentiatisupporting

confidence: 81%

Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage

Hofstetter¹,

Kampka²,

Huppertz³

et al. 2016

Development

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“…As for H3K4 methylation, it seems to be reversed upon DNA damage. At first, LSD1 (lysine-specific demethylase 1), as well as its Caenorhabditis elegans ortholog Spr-5, is enriched on double-strand break sites and responsible for H3K4me1/2 demethylation, resulting in increased recruitment of repair factors (Mosammaparast et al, 2013;Nottke et al, 2011). In addition, KDM5A and KDM5B, the H3K4me2/3 demethylases, are recruited to damaged DNA to induce loss of H3K4me2/3, and required for efficient DNA repair (Li et al, 2014;Seiler et al, 2011).…”

Section: Methylationmentioning

confidence: 99%

Histone modifications in DNA damage response

Cao

Shen

Zhu

2016

Sci. China Life Sci.

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DNA damage is a relatively common event in eukaryotic cell and may lead to genetic mutation and even cancer. DNA damage induces cellular responses that enable the cell either to repair the damaged DNA or cope with the damage in an appropriate way. Histone proteins are also the fundamental building blocks of eukaryotic chromatin besides DNA, and many types of post-translational modifications often occur on tails of histones. Although the function of these modifications has remained elusive, there is ever-growing studies suggest that histone modifications play vital roles in several chromatin-based processes, such as DNA damage response. In this review, we will discuss the main histone modifications, and their functions in DNA damage response.DNA damage response, histone modifications, chromatin, DNA repair Citation:

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“…This enzyme belongs to the same family of flavin-dependent histone demethylases as LSD1, but it functions through a different mechanism for nucleosome recognition as it does not interact with CoREST (Karytinos et al, 2009). LSD1 and LSD2 represent a prime example of how the same catalytic module (a flavin-dependent amine oxidase) can be associated with unrelated non-catalytic domains in distinct protein complexes (Fang et al, 2010;Mosammaparast et al, 2013;Zhang et al, 2013;Saez et al, 2015). More specifically, LSD2 has been found to bind NPAC, a putative oxidoreductase .…”

Section: Regulatory Proteins Stimulate Modification Activitymentioning

confidence: 99%

Touch, act and go: landing and operating on nucleosomes

et al. 2016

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Chromatin-associated enzymes are responsible for the installation, removal and reading of precise post-translation modifications on DNA and histone proteins. They are specifically recruited to the target gene by associated factors, and as a result of their activity, they contribute in modulating cell identity and differentiation. Structural and biophysical approaches are broadening our knowledge on these processes, demonstrating that DNA, histone tails and histone surfaces can each function as distinct yet functionally interconnected anchoring points promoting nucleosome binding and modification. The mechanisms underlying nucleosome recognition have been described for many histone modifiers and related readers. Here, we review the recent literature on the structural organization of these nucleosome-associated proteins, the binding properties that drive nucleosome modification and the methodological advances in their analysis. The overarching conclusion is that besides acting on the same substrate (the nucleosome), each system functions through characteristic modes of action, which bring about specific biological functions in gene expression regulation.

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The histone demethylase LSD1/KDM1A promotes the DNA damage response

Abstract: The E3 ubiquitin ligase RNF168 recruits LSD1 to DNA damage sites, where it reduces histone methylation upstream of 53BP1 recruitment during the DNA damage response.

Cited by 116 publications

References 70 publications

Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage

Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage

Histone modifications in DNA damage response

Touch, act and go: landing and operating on nucleosomes

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