ATM-Dependent Phosphorylation of ATF2 Is Required for the DNA Damage Response

Bhoumik, Anindita; Takahashi, Shoichi; Breitweiser, Wolfgang; Shiloh, Yosef; Jones, Nic; Ronai, Ze’ev A.

doi:10.1016/j.molcel.2005.04.015

Cited by 160 publications

(146 citation statements)

References 43 publications

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“…In contrast, however, previous studies suggested a tumor-promoting role of ATF2 in melanoma (12)(13)(14)(15)(16)(17). Similarly, Notch1 functions as a tumor suppressor in mouse skin, as opposed to its function as an oncogene in other organs (44).…”

Section: Discussionmentioning

confidence: 91%

“…ATF2 target genes include AP1-responsive genes, such as cyclin A, IFN-␤, and TNF-␣ (9-11). Intriguingly, ATF2 has also been implicated in the DNA damage response, through its phosphorylation by phosphoinositide-3-kinase-related protein kinase, including ATM (12). This phosphorylation is required for intra-S phase checkpoint control and for its colocalization with components of the Mre11-Rad50-Nbs1 (MRN) complex within DNA damage repair foci.…”

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confidence: 99%

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Suppressor role of activating transcription factor 2 (ATF2) in skin cancer

Bhoumik

Fichtman²,

DeRossi³

et al. 2008

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

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Activating transcription factor 2 (ATF2) regulates transcription in response to stress and growth factor stimuli. Here, we use a mouse model in which ATF2 was selectively deleted in keratinocytes. Crossing the conditionally expressed ATF2 mutant with K14-Cre mice (K14.ATF2 f/f ) resulted in selective expression of mutant ATF2 within the basal layer of the epidermis. When subjected to a two-stage skin carcinogenesis protocol [7,12-dimethylbenz[a]anthracene/phorbol 12-tetradecanoate 13-acetate (DMBA/TPA)], K14.ATF2 f/f mice showed significant increases in both the incidence and prevalence of papilloma development compared with the WT ATF2 mice. Consistent with these findings, keratinocytes of K14.ATF2 f/f mice exhibit greater anchorage-independent growth compared with ATF2 WT keratinocytes. Papillomas of K14.ATF2 f/f mice exhibit reduced expression of presenilin1, which is associated with enhanced ␤-catenin and cyclin D1, and reduced Notch1 expression. Significantly, a reduction of nuclear ATF2 and increased ␤-catenin expression were seen in samples of squamous and basal cell carcinoma, as opposed to normal skin. Our data reveal that loss of ATF2 transcriptional activity serves to promote skin tumor formation, thereby indicating a suppressor activity of ATF2 in skin tumor formation.␤-catenin ͉ keratinocyte ͉ presenilin ͉ cyclin D1 ͉ papilloma

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Suppressor role of activating transcription factor 2 (ATF2) in skin cancer

Bhoumik

Fichtman²,

DeRossi³

et al. 2008

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

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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%

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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“…ATM kinase, which is defective in the hereditary cancer-prone disorder ataxia-telangiectasia (A-T), is activated by DSBs and phosphorylates a variety of proteins involved in the DNA damage response, leading to cell cycle checkpoint activation, DNA repair, altered gene expression patterns, and/or apoptosis (26). Among the ATM substrates are several transcription factors, including p53 (29), BRCA-1 (30), ATF2 (31), cyclic AMPresponsive element binding protein (32), E2F1 (33), and nuclear factor-nB regulators NEMO and IKK (34). ATR, which responds to bulky lesions and single-strand DNA generated by stalled replication forks or the DSB repair process, shares many substrates with ATM.…”

Section: ¶-(G/t)gggcgg(g/a)(g/a)(g/t)-3 ¶] Via Threementioning

confidence: 99%

Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase

Olofsson

Kelly

Kim

et al. 2007

Molecular Cancer Research

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Sp1, a transcription factor that regulates expression of a wide array of essential genes, contains two SQ/TQ cluster domains, which are characteristic of ATM kinase substrates. ATM substrates are transducers and effectors of the DNA damage response, which involves sensing damage, checkpoint activation, DNA repair, and/or apoptosis. A role for Sp1 in the DNA damage response is supported by our findings: Activation of ATM induces Sp1 phosphorylation with kinetics similar to H2AX; inhibition of ATM activity blocks Sp1 phosphorylation; depletion of Sp1 sensitizes cells to DNA damage and increases the frequency of double strand breaks. We have identified serine 101 as a critical site phosphorylated by ATM; Sp1 with serine 101 mutated to alanine (S101A) is not significantly phosphorylated in response to damage and cannot restore increased sensitivity to DNA damage of cells depleted of Sp1. Together, these data show that Sp1 is a novel ATM substrate that plays a role in the cellular response to DNA damage. (Mol Cancer Res 2007;5(12):1319 -30)

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ATM-Dependent Phosphorylation of ATF2 Is Required for the DNA Damage Response

Cited by 160 publications

References 43 publications

Suppressor role of activating transcription factor 2 (ATF2) in skin cancer

Suppressor role of activating transcription factor 2 (ATF2) in skin cancer

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

Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase

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