Regulation and Localization of Mismatch Repair Proteins
Regulation and Localization of Mismatch Repair Proteins
批准号:
10704811
负责人:
Joanna E Haye
金额:
$5.3万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-08-01 至 2026-05-31
关键词:
AcetylationAffectBindingBiological AssayChromatinColonComplexDNADNA biosynthesisDefectDependenceDimerizationEndometrial CarcinomaEquipmentEukaryotaFrequenciesGenetic TranscriptionGenomic InstabilityHepatobiliaryHereditary Neoplastic SyndromesHereditary Nonpolyposis Colorectal NeoplasmsHistonesHumanImmunoblot AnalysisInvestigationLysineMaintenanceMalignant NeoplasmsMalignant neoplasm of ovaryMethylationMethyltransferaseMicrosatellite InstabilityMismatch RepairModificationMutagenesisMutagensMutationPathway interactionsPolymerase Chain ReactionPost-Translational Protein ProcessingPrincipal InvestigatorProcessProkaryotic CellsProteinsProteomicsPublicationsPublishingRegulationRepair ComplexRoleSaccharomyces cerevisiaeSiteSmall IntestinesSyndromeTestingTissuesTwo-Hybrid System TechniquesUrinary tractVariantWorkYeastscancer typechromatin immunoprecipitationdemethylationearly onset colon cancerexperimental studygene repairgenome integrityhistone methylationhistone modificationoverexpressionparent grantprogramsrecruitrepair function
中文摘要
摘要:
需要补充设备来执行下面总结的实验。这是
执行父母拨款中概述的实验所必需的。DNA错配修复(MMR)是一种
高度保守的过程。一个有功能的MMR途径对于维持基因组的完整性是必不可少的
而MMR的缺失会导致基因组的不稳定和高等真核生物的癌症。例如,缺陷
MMR基因导致Lynch综合征,这是一种常见的遗传性癌症综合征,导致早期
起病的结肠癌、子宫内膜癌、卵巢癌、小肠癌、肝胆管癌和上段癌
尿路和其他组织。在我们最新出版物中,我们显示了删除
转录调节因子(Not4)和一般控制不可降压因子5(Gcn5)调节
参与MMR的主要复合体MutSα(由Msh2和Msh6组成)的水平。Not4和Gcn5
泛素化和乙酰化各种蛋白质的蛋白质。我们假设这些
蛋白质修饰MutSα,这些修饰影响复合体的稳定性和定位。
需要进行进一步的研究,以更好地了解Not4和Gcn5是如何调节的
这些MMR蛋白。此外,我们之前的实验表明,酵母MutSα在
在DNA复制过程中复制机器的附近。人类MutSα与
通过结合增殖细胞核抗原的复制机制,也识别特定的组蛋白修饰。如何酿造酵母
MutSα被招募到染色质仍然难以捉摸。利用酿酒酵母(S.
,这个项目的目的是:1)进一步研究Gcn5和Not4在调节
MutSα稳定性和2)确定翻译后修饰对MMR蛋白的影响
重新招募到染色质。
英文摘要
Abstract:
An equipment supplement is requested to perform the experiments summarized below. This is
necessary to perform the experiments outlined in the parent grant. DNA mismatch repair (MMR) is a
highly conserved process. A functional MMR pathway is essential for maintaining genome integrity
and loss of MMR results in genome instability and cancer in higher eukaryotes. For example, defects
in MMR genes result in Lynch Syndrome, a common hereditary cancer syndrome resulting in early
onset cancers of the colon, endometrium, ovaries, small intestine, hepatobiliary tract, and upper
urinary tract as well as other tissues. In our most recent publication, we showed that deletion of
Modulator of Transcription (Not4) and General Control Nonderepressible 5 (Gcn5) modulate the
levels of MutSα (consisting of Msh2 and Msh6), the major complex involved in MMR. Not4 and Gcn5
are proteins that ubiquitylate and acetylate various proteins respectively. We hypothesize that these
proteins modify MutSα and that the modifications affect the stability and localization of the complex.
Further studies need to be conducted to gain a better understanding of how Not4 and Gcn5 regulate
these MMR proteins. Additionally, our previous experiments have shown that yeast MutSα is in the
vicinity of the replication machinery during DNA replication. Human MutSα interacts with the
replication machinery by binding PCNA and also recognizes specific histone modifications. How yeast
MutSα is recruited to chromatin remains elusive. Using the yeast Saccharomyces cerevisiae (S.
cerevisiae), this project aims to: 1) further examine the role of Gcn5 and Not4 in the regulation of
MutSα stability and 2) determine the effect of post-translational modifications on MMR protein
recruitment to chromatin.
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Regulation and Localization of Mismatch Repair Proteins
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批准号:10671757
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项目类别:
-
资助金额:$18.75万
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财政年份:2022
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负责人:Joanna E Haye
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依托单位:
海外基金