DNA Damage Signaling Triggers Degradation of Histone Methyltransferases through APC/CCdh1 in Senescent Cells

Takahashi, Akiko; Imai, Yoshinori; Yamakoshi, Kimi; Kuninaka, Shinji; Ohtani, Naoko; Yoshimoto, Shin; Hori, Satoshi; Tachibana, Makoto; Anderton, Emma; Takeuchi, Takashi; Shinkai, Yoichi; Peters, Gordon; Saya, Hideyuki; Hara, Eiji

doi:10.1016/j.molcel.2011.10.018

Cited by 166 publications

(170 citation statements)

References 29 publications

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“…However, because the chromatin adjacent to the damaged DNA needs to be open in order to increase the accessibility of repair proteins, H3K9 methylation has to be reversed to promote the repair process. It has been demonstrated that DNA damage induces the degradation of G9a/GLP, which results in decreased H3K9me2 at the promoters of IL-6 and IL-8 in senescent cells (Takahashi et al, 2012). In addition, H3K9me2/3 demethylases KDM4B and KDM4D are recruited to the DNA damage sites mediated by PARP1, and are responsible for H3K9 demethylation (Khoury-Haddad et al, 2014;Young et al, 2013).…”

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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Section: Methylationmentioning

confidence: 99%

Histone modifications in DNA damage response

Cao

Shen

Zhu

2016

Sci. China Life Sci.

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“…10) or the senescence messaging secretome (SMS; ref. 5), hereafter referred to as SASP, is induced by DDRs (11,12) and contributes positively or negatively to cancer development, depending on the biologic context (13)(14)(15). Because some of the SASP factors, such as interleukin (IL)-6 and plasminogen activator inhibitor-1, are reportedly associated with increased cancer risk in obesity (1, 16), we explored the possibility that SASP may contribute positively to obesityassociated cancer development using the obese mouse as a model system.…”

Section: Introductionmentioning

confidence: 99%

Obesity and Cancer: A Gut Microbial Connection

2014

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Multiple epidemiological studies have revealed that excess bodyweight, such as in people who are overweight or obese (defined by a body mass index higher than 25 kg/m 2 ), is a major risk factor for not only diabetes and cardiovascular diseases but also cancer. Effective strategies for obesity prevention are therefore needed for cancer prevention. However, because the prevalence of excess bodyweight in most developed countries has been increasing markedly over the past several decades, with no signs of abating, alternative approaches are also required to conquer obesity-associated cancer. Therefore, we sought to understand the molecular mechanisms underlying obesity-associated cancer. Although several phenomena have been proposed to explain how obesity increases cancer risk, the exact molecular mechanisms that integrate these phenomena have remained largely obscure. Recently, we have traced the association between obesity and increased cancer risk to gut microbiota communities that produce a DNA-damaging bile acid. The analyses also revealed the role of cellular senescence in cancer, which we have been studying for the past few decades. In this review, we provide an overview of our work and discuss the next steps, focusing on the potential clinical implications of these findings. Cancer Res; 74(7);

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“…Thus, there is a scenario, where the discussed proteins come together and may become involved in each other's regulation. 66,67 The induction and maintenance of pluripotency has traditionally been interpreted to depend on the expression of core pluripotency factors. A more recent, not necessarily contradictory concept interprets pluripotency as an intricate balance between the activities of lineage specifying factors, which on their own would promote a specific developmental direction.…”

Section: Mad2l2mentioning

confidence: 99%

Destabilization of pluripotency in the absence of Mad2l2

et al. 2015

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The induction and maintenance of pluripotency requires the expression of several core factors at appropriate levels (Oct4, Sox2, Klf4, Prdm14). A subset of these proteins (Oct4, Sox2, Prdm14) also plays crucial roles for the establishment of primordial germ cells (PGCs). Here we demonstrate that the Mad2l2 (MAD2B, Rev7) gene product is not only required by PGCs, but also by pluripotent embryonic stem cells (ESCs), depending on the growth conditions. Mad2l2¡/¡ ESCs were unstable in LIF/serum medium, and differentiated into primitive endoderm. However, they could be stably propagated using small molecule inhibitors of MAPK signaling. Several components of the MAPK cascade were up-or downregulated even in undifferentiated Mad2l2 ¡/¡ ESCs. Global levels of repressive histone H3 variants were increased in mutant ESCs, and the epigenetic signatures on pluripotency-, primitive endoderm-, and MAPK-related loci differed. Thus, H3K9me2 repressed the Nanog promoter, while the promoter of Gata4 lost H3K27me3 and became de-repressed in LIF/serum condition. Promoters associated with genes involved in MAPK signaling also showed misregulation of these histone marks. Such epigenetic modifications could be indirect consequences of mutating Mad2l2. However, our previous observations suggested the histone methyltransferases as direct (G9a) or indirect (Ezh2) targets of Mad2l2. In effect, the intricate balance necessary for pluripotency becomes perturbed in the absence of Mad2l2.

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DNA Damage Signaling Triggers Degradation of Histone Methyltransferases through APC/CCdh1 in Senescent Cells

Cited by 166 publications

References 29 publications

Histone modifications in DNA damage response

Histone modifications in DNA damage response

Obesity and Cancer: A Gut Microbial Connection

Destabilization of pluripotency in the absence of Mad2l2

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