Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway

Ziv, Yael; Bielopolski, Dana; Galanty, Yaron; Lukas, Claudia; Taya, Yoichi; Schultz, D.; Lukáš, Jiří; Bekker‐Jensen, Simon; Bártek, Jiří; Shiloh, Yosef

doi:10.1038/ncb1446

Cited by 655 publications

(747 citation statements)

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“…It is becoming evident that while the cellular response to DNA damage relies on a core of DDR-dedicated proteins, many of its arms are based on temporary recruitment of proteins or functional modules that normally operate in other processes. Indeed, it has been shown that the DDR temporarily calls into action proteins that normally act in other contexts, such as gene expression [29][30][31][32][33][34][35] or RNA metabolism [36]. This means that the DDR pulls players from various cellular processes out of their regular context and assigns them temporary tasks under its command.…”

Section: Open Access Under CC By-nc-nd Licensementioning

confidence: 99%

“…DNA repair is no exception, and dynamic changes in chromatin condensation and accompanying histone marks have been recognized as inevitable DDR pathways [15,[75][76][77][78][79][80]. Here, too, the DDR relies on recruitment of existing players in the chromatin organization arena [32][33][34][75][76][77][78][79][81][82][83][84][85]. H2B monoubiquitylation was previously implicated in the DDR in the budding yeast [86][87][88].…”

Section: Rnf20-rnf40 Is Called To Emergency Action Upon Dna Damage Inmentioning

confidence: 99%

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RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

et al. 2011

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a b s t r a c tThe DNA damage response (DDR) is emerging as a vast signaling network that temporarily modulates numerous aspects of cellular metabolism in the face of DNA lesions, especially critical ones such as the double strand break (DSB). The DDR involves extensive dynamics of protein post-translational modifications, most notably phosphorylation and ubiquitylation. The DSB response is mobilized primarily by the ATM protein kinase, which phosphorylates a plethora of key players in its various branches. It is based on a core of proteins dedicated to the damage response, and a cadre of proteins borrowed temporarily from other cellular processes to help meet the challenge. A recently identified novel component of the DDR pathway -histone H2B monoubiquitylationexemplifies this principle. In mammalian cells, H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. Generation of monoubiquitylated histone H2B (H2Bub) has been known to be coupled to gene transcription, presumably modulating chromatin decondensation at transcribed regions. New evidence indicates that the regulatory function of H2Bub on gene expression can selectively enhance or suppress the expression of distinct subsets of genes through a mechanism involving the hPAF1 complex and the TFIIS protein. This delicate regulatory process specifically affects genes that control cell growth and genome stability, and places RNF20 and RNF40 in the realm of tumor suppressor proteins. In parallel, it was found that following DSB induction, the H2B monoubiquitylation module is recruited to damage sites where it induces local H2Bub, which in turn is required for timely recruitment of DSB repair protein and, subsequently, timely DSB repair. This pathway represents a crossroads of the DDR and chromatin organization, and is a typical example of how the DDR calls to action functional modules that in unprovoked cells regulate other processes. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. The DNA damage response: borrowing functional modules in an emergencyCellular metabolism is controlled by numerous, interlocked signaling networks. These networks are constantly responding to internal and external stimuli related to the cell's normal life cycle and functions, and to threats to its well being. A major threat to cellular homeostasis is subversion of its genomic stability, which may lead to undue cell death or to neoplasia [1,2]. DNA damage caused by internal or external damaging agents is a major danger to the integrity of the cellular genome. The cellular defense system against this threat is the DNA damage response (DDR) -an elaborate signaling network activated by DNA damage, which swiftly modulates many physiological processes [3,4]. A strong trigger of the DDR is the DNA double-strand break (DSB) [5,6]. DSBs are induced by ionizing radiation, radiomimetic chemicals, reactive oxygen species formed in the course of normal metabolism, and can also result from replic...

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Section: Open Access Under CC By-nc-nd Licensementioning

confidence: 99%

Section: Rnf20-rnf40 Is Called To Emergency Action Upon Dna Damage Inmentioning

confidence: 99%

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

et al. 2011

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“…Identification of ATM-dependent chromatin relaxation via KAP-1 activity following DNA damage has further demonstrated the dependence of DNA repair on alteration of chromatin structure. ATM phosphorylates KAP-1 on Ser 824, and ablation of this site was demonstrated to abolish DSB-induced chromatin relaxation and resulted in cellular hypersensitivity to DSB-inducing agents (Ziv et al, 2006). Moreover, ATM has also been implicated in regulating ordered chromatin changes after DNA breaks to facilitate DNA repair (Berkovich et al, 2007).…”

Section: Defective Dna Dsb Responses and A-t-related Syndromesmentioning

confidence: 99%

DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

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Normal development of an organism requires the ability to respond to DNA damage. A particularly deleterious lesion is a DNA double-strand break (DSB). The cellular response to DNA DSBs occurs via an integrated sensing and signaling network that maintains genomic stability. The outcomes of defective DNA DSB repair are related to the developmental stage of an organism, and often show striking tissue specificity. Many human diseases are associated with deficiencies in DNA DSB repair and can be characterized by neuropathology, immune deficiency, growth retardation or predisposition to cancer. This review will focus on the requirements of the DNA DSB response that function to maintain homeostasis during mammalian development.

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“…Such pleiotropic effects of ATM are attributable to a wide range of its substrates including Chk2, p53, mdm2, NBS1, SMC1, FANCD2, Kap1, BRCA1 and others, all components of DNA damage signalling, repair, chromatin remodelling, transcriptional regulation, apoptosis and other mechanisms that together constitute the multifaceted cellular response to DNA damage (Shiloh, 2003;Ziv et al, 2006;Matsuoka et al, 2007). Consistent with its role in genome stability maintenance, ATM is also an established tumour suppressor whose mutations or epigenetic silencing contributes to pathogenesis of a range of malignancies (Shiloh, 2003;Kastan and Bartek, 2004).…”

Section: Introductionmentioning

confidence: 99%

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

et al. 2007

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The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P ¼ 0.0003) and BRCA2 (30%; P ¼ 0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P ¼ 0.0002), progesterone receptor (PR) negative (P ¼ 0.004) and were of higher grade (P ¼ 0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P ¼ 0.0006) and p53 was overabundant (47%; Po0.0000000001) among the difficult-to-treat ER/PR/ ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.

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Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway

Cited by 655 publications

References 35 publications

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

DNA double-strand break repair and development

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

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