ATM FUNCTION DURING V(D)J RECOMBINATION
V(D)J 重组期间的 ATM 功能
基本信息
- 批准号:8774161
- 负责人:
- 金额:$ 38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-12-02 至 2018-11-30
- 项目状态:已结题
- 来源:
- 关键词:ATM functionAntigen ReceptorsAtaxia-Telangiectasia-Mutated protein kinaseBinding ProteinsCell DeathCellsChromatinChromatin StructureChromosomal translocationChromosome DeletionDNADNA DamageDNA Double Strand BreakDNA Repair PathwayDefectDouble Strand Break RepairEnsureExcisionExonsG1 PhaseG2 PhaseGenome StabilityGenomic InstabilityHealthHistonesIndividualLeadLesionLymphocyteMalignant NeoplasmsMediatingMusNonhomologous DNA End JoiningOncogenicPathway interactionsPost-Translational Protein ProcessingProcessProtein DeficiencyProteinsReceptor GeneRegulationResectedResolutionSequence HomologyStructureTestingTissuesV(D)J RecombinationVariantendonucleaseexpectationhomologous recombinationinsightnovelnovel strategiesnucleasepreventrepairedresponse
项目摘要
DESCRIPTION (provided by applicant): Each individual generates over one billion RAG-mediated DNA double strand breaks (DSBs) every day as developing lymphocytes assemble antigen receptor genes. These DSBs are repaired by the non-homologous end joining (NHEJ) DSB repair pathway to complete the second exon of all antigen receptor genes. Even if NHEJ functioned with near perfect efficiency, thousands of RAG DSBs could persist un-repaired each day. RAG DSBs are generated in G1-phase developing lymphocytes and like other DNA breaks generated in G1, they activate the ATM kinase, which orchestrates DSB responses and repair. ATM deficiency causes a partial block in normal RAG DSB repair and a significant increase in the aberrant repair of RAG DSBs as potentially oncogenic chromosomal translocations and deletions. This suggested to us that in addition to promoting normal RAG DSB repair (the focus of our original proposal), ATM might also regulate novel pathways that function primarily to prevent un-repaired RAG DSBs from being aberrantly repaired. We reasoned that deficiencies of proteins in these pathways would lead to an increase in genomic instability and cancer without causing overt defects in NHEJ-mediated DSB repair. Indeed, deficiency of the histone protein H2AX conforms to this expectation. H2AX is phosphorylated by ATM (forming γ-H2AX) in chromatin at great distances flanking DSBs including RAG DSBs. γ-H2AX is not required for general RAG DSB repair. Rather, we have shown that γ-H2AX prevents un-repaired RAG DSBs from being aberrantly resected by CtIP, the nuclease that initiates DSB repair by homologous recombination (HR) in S-G2. These resected DNA ends cannot be normally joined by NHEJ, but they can be joined by aberrant pathways that form chromosome deletions and translocations using homologies at the broken DNA ends. Thus, H2AX is part of a pathway that preserves the structure of broken DNA ends (by ATM- mediated γ-H2AX formation) until they are either normally joined by NHEJ or activate p53-mediated cell death. We will elucidate the components of this H2AX-dependent pathway and determine the mechanisms by which they preserve DNA end structure in G1. Moreover, we will identify the pathway responsible for aberrant RAG DSB repair, which we believe results from the inappropriate co- activation of NHEJ and HR pathways in G1-phase cells. Completion of these studies will provide important new insights into novel pathways that preserve genomic stability in lymphocytes assembling antigen receptor genes and into the mechanisms that promote aberrant RAG DSB resolution as potentially oncogenic chromosomal translocations and deletions. As the requirements for RAG DSB repair are similar to the NHEJ-mediated repair of other types of DSBs, our findings will be relevant to DSB repair and genome stability in a broad variety of tissues.
描述(由申请人提供):随着发育中的淋巴细胞组装抗原受体基因,每个个体每天产生超过10亿个RAG介导的DNA双链断裂(DSB)。这些DSB通过非同源末端连接(NHEJ)DSB修复途径修复,以完成所有抗原受体基因的第二外显子。即使NHEJ以近乎完美的效率运行,每天仍有数千个RAG DSB无法修复。RAG DSB在G1期发育的淋巴细胞中产生,与G1期产生的其他DNA断裂一样,它们激活ATM激酶,ATM激酶协调DSB反应和修复。ATM缺陷导致正常RAG DSB修复的部分阻断和RAG DSB异常修复的显著增加,如潜在的致癌染色体易位和缺失。这向我们表明,除了促进正常的RAG DSB修复(我们最初建议的重点),ATM还可能调节主要用于防止未修复的RAG DSB被异常修复的新途径。我们推断,这些途径中蛋白质的缺陷将导致基因组不稳定性和癌症的增加,而不会导致NHEJ介导的DSB修复的明显缺陷。事实上,组蛋白H2 AX的缺乏符合这一预期。H2 AX在染色质中被ATM磷酸化(形成γ-H2 AX),在包括RAG DSB的DSB侧翼的很远距离处。一般RAG DSB修复不需要γ-H2 AX。相反,我们已经表明γ-H2 AX防止未修复的RAG DSB被CtIP异常切除,CtIP是通过S-G2中的同源重组(HR)启动DSB修复的核酸酶。这些切除的DNA末端不能通过NHEJ正常连接,但它们可以通过异常途径连接,这些异常途径使用断裂DNA末端处的同源性形成染色体缺失和易位。因此,H2 AX是保留断裂DNA末端结构(通过ATM介导的γ-H2 AX形成)的途径的一部分,直到它们通过NHEJ正常连接或激活p53介导的细胞死亡。我们将阐明这种H2 AX依赖性途径的组成部分,并确定它们在G1中保留DNA末端结构的机制。此外,我们将确定负责异常RAG DSB修复的途径,我们认为这是G1期细胞中NHEJ和HR途径不适当共激活的结果。 这些研究的完成将提供重要的新的见解,以保持淋巴细胞组装抗原受体基因的基因组稳定性的新途径,并进入机制,促进异常RAG DSB决议作为潜在的致癌染色体易位和缺失。由于RAG DSB修复的要求与其他类型DSB的NHEJ介导的修复相似,因此我们的发现将与多种组织中的DSB修复和基因组稳定性相关。
项目成果
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