Break-induced replication and genome rearrangements
断裂诱导的复制和基因组重排
基本信息
- 批准号:9278184
- 负责人:
- 金额:$ 31.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2018-05-31
- 项目状态:已结题
- 来源:
- 关键词:Biological AssayCell Cycle RegulationCellsCellular Metabolic ProcessChromosomal BreaksChromosomesDNADNA DamageDNA Double Strand BreakDNA RepairDNA biosynthesisDirect RepeatsDouble Strand Break RepairERCC1 geneElementsEventFrequenciesGenesGeneticGenetic Crossing OverGenetic RecombinationGenomeHumanLaboratoriesLeadLengthLesionLoss of HeterozygosityMethodsMismatch RepairMitosisMitoticMitotic RecombinationMonitorNormal CellOutcomeProcessRegulationReportingResolutionRoleSiteStructureSystemTelomeraseTestingYeast Model Systemcarcinogenesischromosome losscytotoxicexperimental studygenome integrityhelicasehomologous recombinationhuman diseasenucleasepreventpublic health relevancerepairedsegregationtelomeretumor
项目摘要
DESCRIPTION (provided by applicant):
SUMMARY Chromosomal double strand breaks (DSBs) are cytotoxic lesions that occur spontaneously during normal cell metabolism or by treatment of cells with DNA-damaging agents. If unrepaired or repaired inappropriately, DSBs can lead to mutagenic events, such as chromosome loss, deletions, duplications or translocations, events that can lead to carcinogenesis. The repair of DSBs by homologous recombination (HR) relies on the presence of a homologous duplex to template repair of the broken chromosome and is generally considered to be an error-free mechanism. However, HR can lead to a local loss of heterozygosity (LOH) if the recombining sequences are not identical, and to extensive LOH if repair is associated with a crossover between chromosome homologs. Furthermore, if a repeated sequence at an ectopic site is utilized as the sequence donor and recombination is associated with crossing over, translocations can occur. When both ends of the DSB share homology with the donor duplex sequence, HR proceeds by a two-ended mechanism resulting in primarily non-crossover products. However, if coordination of the two ends is not maintained or only one end of the break is available, such as at a critically short telomere, repair can occur
by break-induced replication (BIR). In this case, following strand invasion replication can extend for more than 100 kb to reach the end of the chromosome. This can cause extensive LOH or non-reciprocal translocation if invasion occurs at a dispersed repeated sequence. In this proposal we will continue mechanistic studies to understand how LOH and chromosome rearrangements occur by BIR or by resolution of recombination intermediates using the yeast model system. The specific aims are: (1) A new system to monitor BIR repair of a chromosomal DSB will be used to determine the mechanism of DNA synthesis and test the idea that destabilization of the ssDNA intermediate decreases BIR efficiency. In addition, we plan to use the iPOND method to identify new factors involved in BIR by association with nascent DNA strands. (2) We will establish a new assay to detect template switching between artificial or natural repeats and identify genes that regulate this process. (3) We will determine the consequences of mis-regulation of structure-selective nucleases on DSB induced and spontaneous mitotic crossovers, and follow the fate of unresolved recombination intermediates during mitosis. The roles of mismatch repair, Rad1-Rad10 and the Mph1 helicase in controlling crossovers will also be determined.
描述(由申请人提供):
摘要染色体双链断裂(DSB)是在正常细胞代谢过程中或用DNA损伤剂处理细胞时自发发生的细胞毒性损伤。如果不修复或修复不当,DSB可能会导致突变事件,如染色体丢失、缺失、复制或易位,这些事件可能导致癌症发生。通过同源重组(HR)修复DSB依赖于断裂染色体模板修复的同源双链的存在,通常被认为是一种无错误的机制。然而,如果重组序列不完全相同,HR会导致局部杂合性丢失(LOH),如果修复与染色体同源之间的交叉相关,则会导致广泛的LOH。此外,如果异位位点的重复序列被用作序列供体,并且重组与交换相关,则可能发生易位。当DSB的两端与供体双链序列同源时,HR通过双端机制进行,主要产生非交叉产物。然而,如果两端的协调不保持或仅有断裂的一端可用,例如在极短的端粒处,则可能发生修复
通过断裂诱导复制(BIR)。在这种情况下,链入侵后的复制可以延伸到超过100kb的染色体末端。如果侵袭发生在分散的重复序列,这可能会导致广泛的LOH或非互换易位。在这项提案中,我们将继续进行机制研究,以了解杂合性缺失和染色体重排是如何通过BIR或通过使用酵母模型系统分解重组中间产物而发生的。其具体目标是:(1)一个新的监测染色体DSB的BIR修复的系统将被用来确定DNA合成的机制,并检验单链DNA中间体的不稳定会降低BIR效率的观点。此外,我们计划使用iPOND方法通过与新生的DNA链相关联来识别参与BIR的新因素。(2)我们将建立一种新的检测方法来检测人工或自然重复序列之间的模板切换,并确定调控这一过程的基因。(3)我们将确定结构选择核酸酶的错误调控对DSB诱导的和自发的有丝分裂交换的后果,并跟踪有丝分裂过程中未分解的重组中间产物的命运。错配修复、Rad1-Rad10和Mph1解旋酶在控制交叉中的作用也将被确定。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Template switching during break-induced replication is promoted by the Mph1 helicase in Saccharomyces cerevisiae.
- DOI:10.1534/genetics.114.162297
- 发表时间:2014-04
- 期刊:
- 影响因子:3.3
- 作者:Stafa A;Donnianni RA;Timashev LA;Lam AF;Symington LS
- 通讯作者:Symington LS
Sgs1 and Exo1 suppress targeted chromosome duplication during ends-in and ends-out gene targeting.
- DOI:10.1016/j.dnarep.2014.07.004
- 发表时间:2014-10
- 期刊:
- 影响因子:3.8
- 作者:Štafa A;Miklenić M;Zunar B;Lisnić B;Symington LS;Svetec IK
- 通讯作者:Svetec IK
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Lorraine S Symington其他文献
Lorraine S Symington的其他文献
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{{ truncateString('Lorraine S Symington', 18)}}的其他基金
Rad52-dependent recombination in response to replication stress
响应复制压力的 Rad52 依赖性重组
- 批准号:
9894801 - 财政年份:2019
- 资助金额:
$ 31.2万 - 项目类别:
Mechanism and regulation of DNA double-strand break repair
DNA双链断裂修复机制及调控
- 批准号:
10623591 - 财政年份:2018
- 资助金额:
$ 31.2万 - 项目类别:
Mechanism and regulation of DNA double-strand break repair
DNA双链断裂修复机制及调控
- 批准号:
10174946 - 财政年份:2018
- 资助金额:
$ 31.2万 - 项目类别:
Mechanism and regulation of DNA double-strand break repair
DNA双链断裂修复机制及调控
- 批准号:
10407594 - 财政年份:2018
- 资助金额:
$ 31.2万 - 项目类别:
Break-induced replication and genome rearrangements
断裂诱导的复制和基因组重排
- 批准号:
8881215 - 财政年份:2010
- 资助金额:
$ 31.2万 - 项目类别:
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