ATF2 in DNA damage response.
ATF2 在 DNA 损伤反应中的作用。
基本信息
- 批准号:7288262
- 负责人:
- 金额:$ 44.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-09-19 至 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATF2 geneATM activationAffectApoptosisAttenuatedCell CycleCell Cycle RegulationCell DeathCell LineCell physiologyChromatinComplexConditionConsensusCutaneous MelanomaDNA DamageDNA Double Strand BreakDNA repair proteinDataDevelopmentDoseEquilibriumEventFamilyFission YeastFoundationsGeneticGenetic ModelsGenetic TranscriptionGrowthH2AFX geneHTATIP geneHistone AcetylationHistone H2AHistonesHomologous GeneHumanHypersensitivityIonizing radiationJNK-activating protein kinaseJUN geneLinkLocalizedLymphocyteMAPK14 geneMammalian CellMediatingMelanoma CellModelingModificationMusMutagenesisNBS1 geneOrganismPathway interactionsPhasePhosphorylationPhosphotransferasesPhysiologicalPredispositionProteinsRateRecruitment ActivityRegulatory PathwayRelative (related person)Research PersonnelResistanceRoleSignal PathwaySignal TransductionSignaling MoleculeSiteStagingStressTestingTumorigenicitybZIP Proteincell growthchromatin remodelinghistone acetyltransferasehuman H2AX proteinhuman HTATIP proteinmelanomamembermouse modelmutantneoplastic cellnovelrepairedresponsetranscription factortumortumorigenesis
项目摘要
DESCRIPTION (provided by applicant): The transcription factor ATF2 contributes to cell cycle and cell death decisions upon its phosphorylation by stress kinases. We recently discovered that ATM phosphorylates ATF2 on Ser490/8 following the formation of double-stranded DNA breaks (DSBs) by ionizing radiation (IR). Consequently, ATF2 is rapidly recruited to DSB-induced foci, where it co-localizes with gamma-H2AX as well as with DNA repair proteins such as Mre11, Rad50 and NBS1 (MRN). Inhibition of ATF2 expression impairs recruitment of Mre11 and NBS1 to the repair foci and attenuates the S-phase checkpoint, and results in hypersensitivity to IR. Furthermore, ATF2 is also required for the activation of ATM, and consequently of Chk1 and Chk2. Significantly, the newly identified role of ATF2 in DNA damage response does not require its transcriptional activity. These findings provide the foundation for our hypothesis that via distinct regulatory pathways (ATM vs. JNK/p38) ATF2 contributes to separate cellular functions: transcription,and DNA damage response and consequently, tumorigenesis. We will test this hypothesis by characterizing the requirements and the mechanism(s) underlying the newly identified function of ATF2 as a regulator of the DNA damage response as it pertains to normal cellular growth and tumorigenesis. Specifically we will: (1) Characterize ATF2 as a regulator of DNA damage in the context of histone modification and ATM activation. Earlier studies established ATF2 association with components of TIP60 histone acetyltransferase complex; ATF2 homologues in S. pombe are implicated in chromatin remodeling, which is now linked with the activation of ATM. We will characterize the role of ATF2 in histone acetylation and the induction of ATM in response to DSB; (2) Utilize fission yeast as a model to genetically dissect ATF2 homolog (Atf21, Pcr1) functions in DNA damage responses. Fission yeast has long provided a paradigm for cell cycle control and DNA damage responses. The stress signaling molecules, including ATF2, are conserved in this organism, and its genetic simplicity will be utilized to independently further develop our preliminary data and to act as a genetic model to test chromatin modifications in a well defined and controlled setting; (3) Determine the effect of p38/JNK on ATM phosphorylation of ATF2 (and vice versa) in relation to ATF2 activity in transcription and the DNA damage response in non-transformed and in tumor cells; (4) Assess which of ATF2 modifications and functions (transcription/damage response) is required for its regulation of the cell cycle, growth control, apoptosis, and tumorigenicity in non transformed and in melanoma cell lines; (5) Determine changes in the skin and melanoma tumor formation and in rate of mutagenesis in mice expressing transcriptional or ATM-mutant forms of ATF2. Overall, using the powerful genetics of S. Pombe, the relevant mammalian cell cultures combined with genetic mouse models our proposal will provide important new understanding of ATF2 in transcription and DNA damage response.
描述(申请人提供):转录因子ATF2参与细胞周期和细胞死亡的决定时,其磷酸化应激蛋白。我们最近发现,ATM在电离辐射(IR)作用下形成双链DNA断裂(DSB)后,使Ser490/8上的ATF2磷酸化。因此,ATF2迅速被招募到DSB诱导的灶中,在那里它与伽马-H_2AX以及DNA修复蛋白如Mre11、Rad50和NBS1(MRN)共定位。抑制ATF2的表达会损害mre11和nbs1向修复灶的募集,减弱S时相检查点,从而导致对IR的超敏反应。此外,ATM的激活也需要ATF2,因此Chk1和Chk2的激活也需要ATF2。值得注意的是,新发现的ATF2在DNA损伤反应中的作用并不需要它的转录活性。这些发现为我们的假设提供了基础,即ATF2通过不同的调控途径(ATM和JNK/p38)促进不同的细胞功能:转录和DNA损伤反应,从而导致肿瘤发生。我们将通过表征新发现的ATF2作为DNA损伤反应调节因子的要求和机制(S)来检验这一假设,因为它与正常的细胞生长和肿瘤发生有关。具体地说,我们将:(1)在组蛋白修饰和ATM激活的背景下,将ATF2描述为DNA损伤的调节因子。早期的研究证实ATF2与Tip60组蛋白乙酰转移酶复合体的组成成分有关;S.pombe中的ATF2同源物与染色质重塑有关,现在被认为与ATM的激活有关。我们将研究ATF2在组蛋白乙酰化中的作用以及DSB对ATM的诱导;(2)利用分裂酵母作为模型,从基因上剖析ATF2同源物(Atf21,PCR1)在DNA损伤反应中的功能。分裂酵母长期以来为细胞周期控制和DNA损伤反应提供了一个范例。应激信号分子,包括ATF2,在这个生物体中是保守的,它的遗传简单性将被用来独立地进一步发展我们的初步数据,并作为一个遗传模型来在定义和控制良好的环境中测试染色质的修饰;(3)确定p38/JNK在转录中对ATF2的ATM磷酸化(反之亦然)的影响与未转化和肿瘤细胞中的ATF2活性和DNA损伤反应有关;(4)评估在未转化和黑色素瘤细胞系中,ATF2的哪一种修饰和功能(转录/损伤反应)是其调控细胞周期、生长控制、细胞凋亡和致瘤性所必需的;(5)测定表达ATF2转录或ATM突变形式的小鼠皮肤和黑色素瘤的肿瘤形成和突变率的变化。总体而言,利用S.Pombe强大的遗传学,相关的哺乳动物细胞培养与遗传小鼠模型相结合,我们的提议将为我们对ATF2在转录和DNA损伤反应中的重要新理解提供重要的新知识。
项目成果
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Ze'ev A Ronai其他文献
Ze'ev A Ronai的其他文献
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{{ truncateString('Ze'ev A Ronai', 18)}}的其他基金
Control of Protein Synthesis by the UPS Under Stress
应激状态下 UPS 对蛋白质合成的控制
- 批准号:
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- 资助金额:
$ 44.76万 - 项目类别:
Control of Protein Synthesis by the UPS Under Stress
应激状态下 UPS 对蛋白质合成的控制
- 批准号:
9301496 - 财政年份:2016
- 资助金额:
$ 44.76万 - 项目类别:
Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance
黑色素瘤转移和耐药性之间的信号重新连接
- 批准号:
10080714 - 财政年份:2016
- 资助金额:
$ 44.76万 - 项目类别:
Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance
黑色素瘤转移和耐药性之间的信号重新连接
- 批准号:
8955610 - 财政年份:2016
- 资助金额:
$ 44.76万 - 项目类别:
Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance
黑色素瘤转移和耐药性之间的信号重新连接
- 批准号:
9213360 - 财政年份:2016
- 资助金额:
$ 44.76万 - 项目类别:
Control of Protein Synthesis by the UPS Under Stress
应激状态下 UPS 对蛋白质合成的控制
- 批准号:
9512865 - 财政年份:2016
- 资助金额:
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