Shu complex and RAD52 function in DNA damage recognition and subsequent repair
Shu 复合物和 RAD52 在 DNA 损伤识别和后续修复中发挥作用
基本信息
- 批准号:10864084
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffinityAlkylating AgentsAlkylationAreaAtomic Force MicroscopyBRCA2 geneBindingBiochemicalBiological AssayBiophysicsBypassCRISPR/Cas technologyCancer CenterCellsCellular biologyComplexDNADNA DamageDNA Double Strand BreakDNA lesionDNA replication forkDNA-Directed RNA PolymeraseDataDevelopmentERCC6 geneElectrophoretic Mobility Shift AssayEnvironmentEquilibriumFilamentFluorescence AnisotropyFluorescence MicroscopyFluorescence Resonance Energy TransferGenetic TranscriptionGenomic InstabilityGoalsGrantHealthHumanHybridsIn VitroInvestigationKnock-outLabelLaboratoriesLeadLesionMalignant NeoplasmsMediatingMentorsMolecularPathway interactionsPesticidesPhasePlayProcessProteinsPublicationsRAD52 geneRNARad51 recombinaseRadonRecombinantsResearchResolutionResourcesRoleSeriesSingle-Stranded DNASiteSoilSpecificityStructureTechnical ExpertiseTechniquesTestingTimeTobaccoTrainingTranscription-Coupled RepairUniversitiesWater PurificationWorkWritingYeastsanalogbasebiophysical techniquesdrinkingdrinking waterexperimental studyhomologous recombinationhuman diseaseinsightlaser tweezermembermutantnoveloptic tweezerprogramsprotein complexprototyperepairedreplication stressresponsesingle moleculeskillsstoichiometry
项目摘要
PROJECT SUMMARY/ABSTRACT
Alkylating agents in our environment from tobacco, pesticides, and produced during drinking water purification
cause DNA lesions. These DNA lesions can cause replication fork stalling and lead to DNA double-strand
breaks that are canonically repaired by the homologous recombination (HR) pathway. The RAD51 protein
plays essential functions in the HR pathway and is regulated by proteins including the Shu complex (SWSAP1-
SWS1-PDS5B-SPIDR), BRCA2, RAD52, and CSB. Misregulation of RAD51 regulators leads to genome
instability and cancer. Recent studies from our lab and others identified novel additional roles of these proteins
in non-canonical repair during DNA lesion recognition, response to replication stress, and transcription coupled
repair of replication structures containing R-loops. Mechanistic insight from the yeast Shu complex determined
a role during abasic lesion recognition and RAD51-mediated bypass mechanisms during replication. Our work
shows that like the yeast Shu complex, the human Shu complex is sensitive to the prototype alkylating agent
MMS and depletion of Shu complex components SWSAP1 and SWS1 cause reduced RAD51 foci. Whether
the human Shu complex functions by a similar mechanism is unknown. Both RAD52 and Shu components
SWSAP1 and SWS1 function during replication restart by an unknown mechanism. RAD52 may use its
annealing functions during replication restart and R-loop resolution. The overall goal of this proposed research
is to determine how the human Shu complex functions at stalled replication forks to recognize abasic lesions
thus enabling either RAD51-dependent strand exchange or RAD52-dependent annealing repair activities. The
experiments proposed in this research program will be conducted in two phases. During the mentored K99
phase, I will determine how the Shu complex functions to recognize alkylation-induced lesions like abasic
lesions and modulate RAD51-dependent repair using training in cell biology, atomic force microscopy (AFM)
and correlative optical tweezers-fluorescence microscopy (CTFM) techniques (Aim 1). During the mentored
phase the candidate will take advantage of co-mentoring, resources available at the University of Pittsburgh
and the UPMC Hillman Cancer Center for professional development to utilize these skills through research,
mentoring, data presentation, and writing opportunities. During the independent R00 phase of the research
program, technical skills obtained during the K99 phase will be applied to elucidate the role of Shu complex in
RAD52-mediated replication fork restart (Aim 2). Also, during the R00 phase I will extend these approaches
into a new area involving resolution of RNA-DNA hybrids by RAD52 protein complexes. These experiments will
provide me with the data required for an early independent publication and preliminary data for R-series grants.
Importantly, during the R00 phase the candidate will develop independence from their mentor and co-mentors
by focusing on the dynamic interplay between the Shu complex and RAD52 in response to replication stress.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sarah R Hengel其他文献
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{{ truncateString('Sarah R Hengel', 18)}}的其他基金
Shu complex and RAD52 function in DNA damage recognition and subsequent repair
Shu 复合物和 RAD52 在 DNA 损伤识别和后续修复中发挥作用
- 批准号:
10535461 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
Shu complex and RAD52 function in DNA damage recognition and subsequent repair
Shu 复合物和 RAD52 在 DNA 损伤识别和后续修复中发挥作用
- 批准号:
10348466 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
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