Molecular mechanisms of intersecting human telomeric functions
人类端粒功能交叉的分子机制
基本信息
- 批准号:10550394
- 负责人:
- 金额:$ 37.87万
- 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:2023-02-06 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:BindingBiochemicalBiochemistryBiologicalCell ProliferationCellsCellular biologyChromosomesComplexCrystallographyCytoskeletonDNADNA DamageDiseaseEnsureEnzymesFunctional disorderGenetic Crossing OverGenetic RecombinationGenomeGerm CellsHumanInfertilityKnowledgeMalignant NeoplasmsMeiosisMolecularNuclear EnvelopePathway interactionsProcessProductionProteinsRNARibonucleoproteinsS phaseSomatic CellStructureTelomeraseTestingTherapeuticcancer cellgenome integrityhuman diseasenovel therapeutic interventionnovel therapeuticsprotein complexrecruitstem cellsstem-like celltelomeretherapeutic development
项目摘要
Molecular mechanisms of intersecting human telomeric functions
Project Summary/Abstract
Telomeres perform three essential functions in human cells. First, telomeres protect chromosomes against
catastrophic end-to-end fusions by shielding them from the DNA damage sensing pathways. A six-membered
protein complex called shelterin binds specifically to telomeric DNA to afford end protection. Second, telomeres
facilitate end replication, allowing proliferating cells like stem/progenitor cells and cancer cells to replenish
chromosome ends. A complex ribonucleoprotein enzyme called telomerase helps solve end replication.
Telomerase facilitates end replication by adding telomeric DNA to chromosome ends using its RNA template.
While telomerase activation in somatic cells is a hallmark of cancer, telomerase dysfunction in stem cells
results in diseases called telomeropathies. Shelterin must protect chromosome ends from illicit DNA fusions
but allow telomerase to access the same ends. A shelterin protein called TPP1 is instrumental in recruiting
telomerase to telomeres, allowing shelterin to facilitate end protection and end replication, but the molecular
mechanism of how TPP1 switches from end-protection mode to end-replication mode during S-phase is not
known. Third, telomeres help homologous chromosomes undergo pairing and meiotic crossover to facilitate
gamete production. To perform this function, telomeres attach to the nuclear envelope with the help of a
meiosis-specific protein complex called TERB1-TERB2-MAJIN and connect with the cytoskeletal force-
generating machinery. This allows chromosomes to move, enabling homologous chromosomes to pair up and
undergo meiotic crossover. Paired meiotic chromosomes must be protected from telomeric recombination at
the nuclear envelope, but how this occurs is not known at the molecular level. Illuminating the molecular
interplay between the three telomeric functions will enrich our understanding of how genome integrity is upheld
and suggest novel therapeutic avenues for diseases like cancers, telomeropathies, and infertility. This proposal
aims to apply the knowledge of telomeres, telomerase, and meiotic assemblies, and expertise in biochemistry,
crystallography, and cell biology to understand how human telomeres perform their three critical functions,
especially in the contexts where these clash with one another. It also aims to discover new factors responsible
for upholding these functions and reveal their underlying biochemical activities. Finally, this proposal aims to
dissect the molecular mechanism of disease caused by the disruption of these functions and test new
strategies for therapeutic development. The proposed approach to dissect the molecular mechanisms of
intersecting telomeric processes will enhance our knowledge of how telomeres enable genome integrity and
suggest therapeutic opportunities to tackle telomere dysfunction in disease.
人类端粒功能交叉的分子机制
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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Jayakrishnan Nandakumar其他文献
Jayakrishnan Nandakumar的其他文献
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{{ truncateString('Jayakrishnan Nandakumar', 18)}}的其他基金
Mechanisms of chromosome motility during mammalian meiosis
哺乳动物减数分裂过程中染色体运动的机制
- 批准号:
10442797 - 财政年份:2022
- 资助金额:
$ 37.87万 - 项目类别:
Mechanisms of chromosome motility during mammalian meiosis
哺乳动物减数分裂过程中染色体运动的机制
- 批准号:
10672204 - 财政年份:2022
- 资助金额:
$ 37.87万 - 项目类别:
The role fo the TPP1 peotein in telomerase function and cancer cell survival
TPP1蛋白在端粒酶功能和癌细胞存活中的作用
- 批准号:
8724761 - 财政年份:2013
- 资助金额:
$ 37.87万 - 项目类别:
The role fo the TPP1 peotein in telomerase function and cancer cell survival
TPP1蛋白在端粒酶功能和癌细胞存活中的作用
- 批准号:
8731837 - 财政年份:2013
- 资助金额:
$ 37.87万 - 项目类别:
Separation-of-function Mutants to Study the Biological Significance of Telomerase
功能分离突变体研究端粒酶的生物学意义
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8298843 - 财政年份:2012
- 资助金额:
$ 37.87万 - 项目类别:
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