Chromosomal consequences of DNA precursor pools imbalances and contamination
DNA 前体库失衡和污染的染色体后果
基本信息
- 批准号:8890840
- 负责人:
- 金额:$ 28.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-06-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAffectAnti-Bacterial AgentsAreaCell CycleCell SurvivalCellsCessation of lifeChestChromosomesComplexDNADNA RepairDNA biosynthesisDNA replication originDNA-Directed DNA PolymeraseDevelopmentDrug DesignDrug FormulationsDrug TargetingEnsureEquilibriumEscherichia coliEventEvolutionFluorouracilFrequenciesFutureGenesGeneticGenetic studyGoalsHealthHumanHypoxanthinesIndividualKineticsLeadLesionMeasuresMedicalMetabolismMicrobeModelingModificationMutagenesisNatureOutcomePathway interactionsPharmaceutical PreparationsPhysiologicalPoisoningPositioning AttributeProcessReplication OriginRoleSourceStagingStarvationSuicideSystemTestingTextThymineTimeToxic effectTranslatingTrimethoprimUracilWorkabstractinganalogantimicrobialbactericidebasecancer therapycell killingdesignfolic acid metabolismgenetic informationgenome analysishydroxyureainsightkillingsmutantnext generationnovelrecombinational repairrepairedtooltransmission processuracil analog
项目摘要
Enter the text here that is the new abstract information for your application. This
section must be no longer than 30 lines of text.
The broad goal of this study is to investigate the chromosomal consequences of cell's
inability to maintain the three critical aspects of the DNA precursors pools: their quantity,
their balance and their purity. Quality of DNA precursor pools has been long recognized
for its important role in avoidance of mutagenesis, which is significant for evolution of
any species. Recently, we have argued for a more immediate consequence of limited,
imbalanced or contaminated DNA precursor pools, which is formation of chromosomal
lesions that threaten cell's survival and that require complex DNA mending system called
"recombinational repair". We have proposed two general models of how base analog
incorporation into DNA could lead to chromosomal fragmentation that requires
recombinational repair. In our previous work, we identified uracil and hypoxanthine as
the major base analogs contaminating DNA precursor pools in E. coli. At the same time,
the identity and the sources of other natural base analogs contaminating DNA precursor
pools remain unknown. Moreover, even though DNA precursor pool imbalance at first
leads to reparable chromosomal lesions, it eventually generates irreparable
chromosomal lesions of unknown nature. Our recent observations provide insights into
the possible scenarios leading to irreparable chromosomal lesions and into the nature of
these lesions, while introduction of genome analysis presents an opportunity to identify
the most affected parts of the chromosome. Aim 1 of this study addresses specific
mechanisms of chromosomal fragmentation, induced by hypoxanthine, uracil or
fluorouracil. Aim 2 focuses on characterization of the mysterious origin DNA
disappearance during thymine starvation, coinciding with thymineless death. Aim 3 tests
our recently-proposed multi-stage model for thymineless death, which begins with
stalling of the existing replication forks, proceeds through unknown number of
intermediate stages and ends with the replication origin destruction. Collectively, this
work will emphasize the importance to keep DNA precursor pools plentiful, balanced and
sanitized by characterizing various sources of imbalance and contamination of the pools,
as well as the chromosomal consequences, including irreparable lesions, that result from
pool contamination and imbalance.
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一节不能超过30行文字。
这项研究的主要目标是研究细胞分裂的染色体后果。
无法维持DNA前体库的三个关键方面:它们的数量,
平衡和纯洁DNA前体库的质量早已得到公认
由于其在避免突变中的重要作用,这对进化具有重要意义。
任何物种。最近,我们主张有限的,
不平衡或污染的DNA前体池,这是染色体的形成,
威胁细胞生存并需要复杂的DNA修复系统的病变称为
“重组修复”。我们提出了两个一般模型,
整合到DNA中可能导致染色体断裂,
重组修复在我们以前的工作中,我们鉴定了尿嘧啶和次黄嘌呤,
污染E.杆菌与此同时,
污染DNA前体的其他天然碱基类似物的身份和来源
游泳池仍然未知。此外,即使DNA前体库最初不平衡,
导致可修复的染色体损伤,最终产生不可修复的
未知性质的染色体病变。我们最近的观察提供了关于
可能的情况下,导致无法弥补的染色体病变,并进入性质,
这些病变,而引入基因组分析提供了一个机会,以确定
染色体中受影响最严重的部分。本研究的目标1涉及具体的
次黄嘌呤、尿嘧啶或
氟尿嘧啶。目标2重点关注神秘起源DNA的表征
在胸腺嘧啶饥饿期间消失,与无胸腺嘧啶死亡同时发生。Aim 3测试
我们最近提出的无胸腺嘧啶死亡的多阶段模型,
现有复制分叉的停止,通过未知数量的
中间阶段,并以复制起点破坏结束。总的来说,这
这项工作将强调保持DNA前体库丰富、平衡和
通过表征池的不平衡和污染的各种来源来净化,
以及染色体的后果,包括不可修复的损伤,
池污染和不平衡。
项目成果
期刊论文数量(0)
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Andrei Kuzminov其他文献
Andrei Kuzminov的其他文献
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{{ truncateString('Andrei Kuzminov', 18)}}的其他基金
Chromosomal death due to misincorporation of wrong material into DNA
由于错误的物质掺入 DNA 导致染色体死亡
- 批准号:
10321611 - 财政年份:2007
- 资助金额:
$ 28.08万 - 项目类别:
Chromosomal consequences of DNA precursor pools imbalances and contamination
DNA 前体库失衡和污染的染色体后果
- 批准号:
9088460 - 财政年份:2007
- 资助金额:
$ 28.08万 - 项目类别:
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