DNA damage response kinase signaling in non-replicating human cells and tissues
非复制人类细胞和组织中的 DNA 损伤反应激酶信号传导
基本信息
- 批准号:10091482
- 负责人:
- 金额:$ 29.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:ATM functionATR geneAdjuvantAgingAntineoplastic AgentsBiological ModelsCancer EtiologyCell CycleCell Cycle ProgressionCell DeathCell Differentiation processCell SurvivalCell divisionCell physiologyCellsChemotherapy-Oncologic ProcedureCultured CellsDNADNA DamageDNA biosynthesisDNA lesionDNA replication forkDNA-Directed DNA PolymeraseDNA-Directed RNA PolymeraseDataDisease susceptibilityERCC3 geneEffectivenessEpidermisEukaryotaEventExhibitsExposure toFoundationsGenetic TranscriptionGenotoxic StressGoalsHealthHoloenzymesHomeostasisHumanHuman bodyIn VitroKRP proteinLeadLifeLinkMalignant NeoplasmsMissionMitoticModelingMovementMusMutagenesisMutagensOrganOutcomePathway interactionsPhasePhase TransitionPhosphotransferasesPhysiologicalPlayPopulationPreventionProcessPropertyProtein KinaseProteinsPublic HealthPublishingRNA Polymerase IIResearchRiskRoleSignal TransductionSkinSkin TissueSourceStressTestingTherapeuticTissuesToxic effectUltraviolet B RadiationUnited States National Institutes of HealthWorkataxia telangiectasia mutated proteinbasebiological adaptation to stresscancer therapycarcinogenesiscell typechemotherapeutic agentenvironmental agentgenotoxicityhomologous recombinationhuman tissueimprovedin vivoinhibitor/antagonistinnovationinsightirradiationkinase inhibitornovelprogramsreplication stressresponsesmall molecule inhibitorstem cell differentiationstressortranscription factor S-IItranscription factor TFIIH
项目摘要
PROJECT SUMMARY/ABSTRACT
The interference of DNA polymerase movement by DNA damage induced by endogenous,
environmental, and chemotherapeutic agents is both a cause of cancer and aging in humans and a common
mechanism of action of many anti-cancer drugs. This genotoxin-associated replication stress is also a well-
recognized activator of the ATR (ataxia telangiectasia-mutated and rad3-related) protein kinase, which plays
critical roles in regulating DNA replication and cell cycle phase transitions during the cellular DNA damage
response (DDR). Small molecule inhibitors of ATR have emerged as potential adjuvants to improve the
effectiveness of common cancer chemotherapy regimens. Unfortunately, our understanding of the role of ATR
in the DDR may be biased towards cellular processes involving DNA synthesis and cell division because of the
model systems of actively replicating cells that are typically used to study ATR function. However, using non-
replicating cultured cells in vitro and human skin tissue explants ex vivo, our preliminary data have revealed a
novel mode of ATR activation that is closely linked with transcription stress and specifically with the XPB subunit
of the multi-functional protein TFIIH (transcription factor II-H). Moreover, we have found that in striking contrast
to the DNA damage-sensitizing effects of ATR kinase inhibition on replicating cells, ATR inhibition in non-
replicating cells instead protects non-replicating cells from the lethal effects of several DNA damaging agents.
The objective of this proposal is to therefore more clearly define the mechanisms of ATR kinase activation and
function in non-replicating human cells and to determine whether ATR inhibitors provide therapeutic benefit to
important cell populations of human tissues exposed to DNA damaging agents. The central hypothesis of this
proposal is that the mechanism of ATR kinase activation in non-replicating cells exhibits unique properties in
comparison to replicating cells and that transcription-associated ATR kinase signaling has profoundly different
effects on cell and tissue fate in response to DNA damage. The rationale for this proposed research is that it will
provide a more complete understanding of how the ATR kinase impacts cellular and tissue responses to DNA
damaging agents in humans and may lead to the use of ATR kinase inhibitors to limit the toxicity of certain DNA
damaging compounds. Our hypothesis will be tested by carrying out the following three specific aims: 1) Define
the mechanism of ATR kinase activation in non-replicating quiescent and differentiated human cells exposed to
genotoxic stress; 2) Characterize the positive and negative consequences of ATR kinase inhibition in non-
replicating cells in vitro; and 3) Validate the modes of ATR kinase activation and function in non-replicating cells
of human and mouse skin tissue ex vivo and in vivo. Our approach is innovative because it will investigate an
unexplored and physiologically relevant aspect of the DNA damage response in human cells and tissues. The
proposed research is significant because it will provide novel mechanistic insights into how modulation of ATR-
dependent DNA damage signaling may provide therapeutic benefits in human cells and tissues.
项目总结/文摘
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Michael George Kemp其他文献
Michael George Kemp的其他文献
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{{ truncateString('Michael George Kemp', 18)}}的其他基金
Mapping DNA Repair and Error-Prone DNA Synthesis in Geriatric Skin
绘制老年皮肤 DNA 修复和容易出错的 DNA 合成图谱
- 批准号:
10253181 - 财政年份:2021
- 资助金额:
$ 29.6万 - 项目类别:
Mapping DNA Repair and Error-Prone DNA Synthesis in Geriatric Skin
绘制老年皮肤 DNA 修复和容易出错的 DNA 合成图谱
- 批准号:
10426239 - 财政年份:2021
- 资助金额:
$ 29.6万 - 项目类别:
DNA damage response kinase signaling in non-replicating human cells and tissues
非复制人类细胞和组织中的 DNA 损伤反应激酶信号传导
- 批准号:
10560511 - 财政年份:2019
- 资助金额:
$ 29.6万 - 项目类别: