Understanding and Targeting the R-Loop-Mediated DNA Damage Response at Telomeres
了解并靶向 R 环介导的端粒 DNA 损伤反应
基本信息
- 批准号:10716512
- 负责人:
- 金额:$ 36.83万
- 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:2023-08-10 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AgingBypassCell AgingCell divisionCellsChemicalsCockayne SyndromeCritical PathwaysCytoprotectionDNA DamageDNA Repair PathwayDNA biosynthesisDNA lesionDNA replication forkDependenceFutureGenomic InstabilityHumanInvestigationLesionLinkLongevityMalignant NeoplasmsMediatingMolecularMusPathway interactionsPatientsPhenotypePremature aging syndromeProcessProteinsRAD52 geneRadiationReactive Oxygen SpeciesRoleSourceStressTelomeraseTelomere PathwayTelomere ShorteningTestingUntranslated RNAanticancer researchcancer cellcancer typecell ageclinical investigationcopingnoveloxidative DNA damageoxidative damagepre-clinicalprotective pathwayrepairedresponsesenescencesensortargeted cancer therapytelomeretelomere losstumorigenesis
项目摘要
Project Summary
Oxidative DNA damage is frequently generated by radiation, chemicals, and endogenous oxygen radicals,
contributing to genomic instability during both aging and tumorigenesis. Oxidative damage at telomeres can
lead to telomere loss or attrition, which triggers cellular senescence and limits the lifespan of dividing cells.
While it is clear that oxygen radicals can inflict multiple types of DNA lesions, how these lesions are repaired at
telomeres is still largely unknown. By inducibly and locally generating reactive oxygen species (ROS) at
telomeres, we discovered a novel DNA repair pathway critical for the protection of cells against telomeric
oxidative damage. This pathway is activated by ROS-induced R-loops, and is mediated by break-induced
replication (BIR), a process that “jumpstarts” DNA synthesis at collapsed replication forks. In parallel with our
studies on the oxidative damage response at telomeres, we also investigated how cancer cells maintain
telomeres to bypass senescence. In particular, we have molecularly dissected the alternative lengthening of
telomere (ALT) pathway, which is used by ~10-15% of human cancers to extend telomeres. Interestingly, we
found that ALT is also an R-loop-triggered and BIR-mediated repair pathway. The unexpected similarities
between the repair pathway dealing with telomeric oxidative damage and the ALT pathway lead us to
hypothesize that these telomere repair pathways are mechanistically linked. Furthermore, cancer cells hijack
the R-loop and BIR-mediated repair pathway to extend telomeres and bypass senescence. In Aim 1, we will
systematically delineate the R-loop and BIR-mediated pathway that repairs telomeric oxidative damage, and
investigate if this pathway contributes to ALT activation in cancer cells. In Aim 2, we will develop strategies to
exploit the cellular dependency on the R-loop and BIR-mediated ALT pathway, which may allow us to
selectively kill ALT+ cancer cells and aged cells harboring high telomeric oxidative damage. Our studies may
establish a new link between cellular aging and tumorigenesis, and provide new opportunities to eliminate
cancer cells by targeting a hijacked DNA repair pathway. These studies may have transformative impacts at
the interface between aging and cancer research, opening a new avenue to future preclinical and clinical
investigations.
项目摘要
氧化性DNA损伤通常由辐射、化学物质和内源性氧自由基产生,
在衰老和肿瘤发生过程中导致基因组不稳定。端粒的氧化损伤
导致端粒丢失或磨损,从而引发细胞衰老并限制分裂细胞的寿命。
虽然很明显,氧自由基可以造成多种类型的DNA损伤,这些损伤是如何修复的,
端粒在很大程度上仍是未知的。通过诱导和局部产生活性氧(ROS),
端粒,我们发现了一种新的DNA修复途径,对于保护细胞免受端粒损伤至关重要。
氧化损伤该途径由ROS诱导的R环激活,并由断裂诱导的
复制(BIR),一个在折叠的复制叉处"启动" DNA合成的过程。与我们的
除了研究端粒的氧化损伤反应外,我们还研究了癌细胞如何维持
端粒绕过衰老。特别是,我们已经从分子上剖析了替代延长的
端粒(ALT)途径,约10 - 15%的人类癌症使用该途径来延长端粒。有趣的是,我们
发现ALT也是R环触发和BIR介导的修复途径。意想不到的相似之处
端粒氧化损伤的修复途径和ALT途径之间的联系使我们
假设这些端粒修复途径是机械连接的。此外,癌细胞劫持
R环和BIR介导的修复途径,以延长端粒和绕过衰老。在目标1中,我们
系统地描述修复端粒氧化损伤的R环和BIR介导的途径,
研究这种途径是否有助于癌细胞中的ALT激活。在目标2中,我们将制定战略,
利用细胞对R环和BIR介导的ALT途径的依赖性,这可能使我们能够
选择性地杀死ALT+癌细胞和携带高端粒氧化损伤的衰老细胞。我们的研究可能
在细胞衰老和肿瘤发生之间建立新的联系,并提供新的机会,
通过靶向被劫持的DNA修复途径。这些研究可能会产生变革性的影响,
衰老和癌症研究之间的接口,为未来的临床前和临床研究开辟了新的途径。
调查事务所
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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Li Lan的其他文献
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{{ truncateString('Li Lan', 18)}}的其他基金
Oxidative DNA base damage and repair at telomeres and the relevance to cell senes
端粒氧化 DNA 碱基损伤和修复及其与细胞功能的相关性
- 批准号:
8566953 - 财政年份:2013
- 资助金额:
$ 36.83万 - 项目类别:
Oxidative DNA base damage and repair at telomeres and the relevance to cell senes
端粒氧化 DNA 碱基损伤和修复及其与细胞功能的相关性
- 批准号:
8689876 - 财政年份:2013
- 资助金额:
$ 36.83万 - 项目类别:
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