Germline mutagenesis at meiotic double-strand breaks
Germline mutagenesis at meiotic double-strand breaks
批准号:
10720403
负责人:
Maria Jasin
金额:
$44.92万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-08-08 至 2028-04-30
关键词:
AddressAdolescentAffectArchitectureBindingBinding SitesBiological AssayCell divisionCellsChromosomal translocationChromosomesCircular DNADNADNA Double Strand BreakDNA Sequence RearrangementDetectionDevelopmentDistantEnsureEventEvolutionExcisionFrequenciesGenerationsGenesGenetic RecombinationGenomeGenomic SegmentGerm CellsHaploidyHealthHomologous GeneHumanLesionMapsMeiosisMeiotic RecombinationMitoticMusMutagenesisMutant Strains MiceMutationNonhomologous DNA End JoiningOutcomePaternal AgePreparationPrevalencePublishingRegulationResectedRiskRoleSPO11 geneSingle-Stranded DNASomatic CellSpermatogenesisSpo11 proteinYeastsage effectagedataxia telangiectasia mutated proteinbaseeggexperienceexperimental studygenome-widehomologous recombinationin vivomalerepairedsegregationsperm celltransmission processyoung adult
中文摘要
项目摘要/摘要
减数分裂重组对哺乳动物生殖细胞的减数分裂是必不可少的,从而对
单倍体配子的发育,即精子和卵子。重组是由数百个DNA双链启动的
链断裂(DSB)引入了由SPO11蛋白催化的全基因组。忠实传输
将基因组传递给后代需要对这些大量的DSB进行适当的修复,主要是通过
与同源基因重组。在减数分裂细胞中,DSB的形成是由ATM激酶调节的,它是
在有丝分裂细胞中是DSB的主要响应者,因此在没有ATM的情况下,减数分裂DSB
增加~10倍。
我们最近发现减数分裂DSB存在引发生殖系重排的风险,在
涉及非同源末端连接的特殊缺失和串联复制,尤其是在缺少
自动取款机。就扰乱这些热点所在的基因而言,这些事件也是重要的
作为相关的PRDM9结合位点,控制这些基因座上的重组。因此,我们的发现揭示了一个
先前隐藏的可能影响人类健康和基因组的生殖系突变潜力
进化论。在人类身上,最近对冰岛人进行的远程测序支持这种影响。这项建议旨在
旨在了解导致这些事件的机制、减数分裂DSB的事件范围以及
年龄的影响。我们假设在减数分裂DSB中可能有比我们已有的重排更多的重排
之前确认过的。因此,在第一个目标中,我们建议确定可以
产生于减数分裂双链断裂,包括远距离缺失、重复和染色体易位。在……里面
第二个目的,我们考察可能影响缺失形成的因素。我们关注的是DNA的作用
结束处理分两步进行,即SPO11去除和结束处理,以及重组。此外,我们还解决了
双链断裂附近形成的间隙是否是同源重组的底物以及父本的影响
减数分裂DSB重排事件的年龄。
英文摘要
Project Summary/Abstract
Meiotic recombination is essential for the reductional cell division in mammalian germ cells and thus for the
development of haploid gametes, i.e., sperm and eggs. Recombination is initiated by hundreds of DNA double-
strand breaks (DSBs) introduced genome-wide that are catalyzed by the SPO11 protein. Faithful transmission
of the genome to subsequent generations requires proper repair of these numerous DSBs, primarily through
recombination with the homolog. DSB formation is regulated in meiotic cells by the ATM kinase, which is
known to be a primary responder to DSBs in mitotic cells, such that in the absence of ATM, meiotic DSBs
increase ~10-fold.
We recently discovered that meiotic DSBs are at risk for provoking germline rearrangements, in
particular deletions and tandem duplications involving nonhomologous end-joining, especially in the absence of
ATM. These events are consequential in terms of disrupting the genes in which these hotspots occur as well
as the associated PRDM9 binding sites that govern recombination at those loci. Thus, our findings reveal a
previously hidden potential for germline mutagenesis that is likely to affect human health and genome
evolution. In humans, recent long-range sequencing of Icelanders supports this impact. This proposal pursues
aims to understand the mechanisms that give rise to these events, the range of events at meiotic DSBs, and
the effect of age. We hypothesize that other rearrangements are possible at meiotic DSBs than what we have
previously identified. Thus, in the first aim, we propose to determine the range of mutagenic outcomes that can
arise from meiotic DSBs, including long-range deletions and duplications and chromosomal translocations. In
the second aim, we examine factors that may impact the formation of deletions. We focus on the effect of DNA
end processing at two steps, SPO11 removal and end processing, and recombination. Further, we address
whether gaps formed at nearby DSBs are substrates for homologous recombination and the impact of paternal
age in the rearrangement events at meiotic DSBs.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Homology-directed repair: BRCA2 and RAD51 paralogs
-
批准号:10697318
-
项目类别:
-
资助金额:$99.94万
-
财政年份:2020
-
负责人:Maria Jasin
-
依托单位:
Homology-directed repair: BRCA2 and RAD51 paralogs
-
批准号:10226333
-
项目类别:
-
资助金额:$101.98万
-
财政年份:2020
-
负责人:Maria Jasin
-
依托单位:
Homology-directed repair: BRCA2 and RAD51 paralogs
-
批准号:10053589
-
项目类别:
-
资助金额:$70.45万
-
财政年份:2020
-
负责人:Maria Jasin
-
依托单位:
Homology-directed repair: BRCA2 and RAD51 paralogs
-
批准号:10447108
-
项目类别:
-
资助金额:$99.94万
-
财政年份:2020
-
负责人:Maria Jasin
-
依托单位:
Homologous recombination mechanisms in mammalian cells
-
批准号:9923699
-
项目类别:
-
资助金额:$55.69万
-
财政年份:2016
-
负责人:Maria Jasin
-
依托单位:
Homologous recombination mechanisms in mammalian cells
-
批准号:9071768
-
项目类别:
-
资助金额:$29.38万
-
财政年份:2016
-
负责人:Maria Jasin
-
依托单位:
Homologous recombination mechanisms in mammalian cells
-
批准号:9475221
-
项目类别:
-
资助金额:$53.14万
-
财政年份:2016
-
负责人:Maria Jasin
-
依托单位:
Fluorescence microscopy for proposed research in the parent grant
-
批准号:9330633
-
项目类别:
-
资助金额:$17.69万
-
财政年份:2016
-
负责人:Maria Jasin
-
依托单位:
HOMOLOGY-DIRECTED DNA REPAIR PROTEINS BRCA2 AND RAD51 IN TUMOR RELEVANT TISSUES
-
批准号:9263924
-
项目类别:
-
资助金额:$36.5万
-
财政年份:2014
-
负责人:Maria Jasin
-
依托单位:
HOMOLOGY-DIRECTED DNA REPAIR PROTEINS BRCA2 AND RAD51 IN TUMOR RELEVANT TISSUES
-
批准号:8686532
-
项目类别:
-
资助金额:$36.24万
-
财政年份:2014
-
负责人:Maria Jasin
-
依托单位:
HOMOLOGY-DIRECTED DNA REPAIR PROTEINS BRCA2 AND RAD51 IN TUMOR RELEVANT TISSUES
-
批准号:9054090
-
项目类别:
-
资助金额:$36.5万
-
财政年份:2014
-
负责人:Maria Jasin
-
依托单位:
HOMOLOGY-DIRECTED DNA REPAIR PROTEINS BRCA2 AND RAD51 IN TUMOR RELEVANT TISSUES
-
批准号:8843401
-
项目类别:
-
资助金额:$36.5万
-
财政年份:2014
-
负责人:Maria Jasin
-
依托单位:
Mechanism and distribution of meiotic recombination initiation in mouse
-
批准号:8047993
-
项目类别:
-
资助金额:$37.39万
-
财政年份:2009
-
负责人:Maria Jasin
-
依托单位:
Double-strand break repair in mammalian cells
-
批准号:7989704
-
项目类别:
-
资助金额:$20.83万
-
财政年份:2009
-
负责人:Maria Jasin
-
依托单位:
Mechanism and distribution of meiotic recombination initiation in mouse
-
批准号:7841873
-
项目类别:
-
资助金额:$38.95万
-
财政年份:2009
-
负责人:Maria Jasin
-
依托单位:
Mechanism and distribution of meiotic recombination initiation in mouse
-
批准号:8459531
-
项目类别:
-
资助金额:$35.48万
-
财政年份:2009
-
负责人:Maria Jasin
-
依托单位:
Mechanism and distribution of meiotic recombination initiation in mouse
-
批准号:8277453
-
项目类别:
-
资助金额:$37.39万
-
财政年份:2009
-
负责人:Maria Jasin
-
依托单位:
BRCA1 and BRCA2: Homology-Directed DNA Repair and Breast Cancer
-
批准号:7438487
-
项目类别:
-
资助金额:$46.38万
-
财政年份:2008
-
负责人:Maria Jasin
-
依托单位:
Role of Spo11 and recombination in mouse meiosis
-
批准号:6361900
-
项目类别:
-
资助金额:$46.79万
-
财政年份:2001
-
负责人:Maria Jasin
-
依托单位:
Role of Spo11 and recombination in mouse meiosis
-
批准号:6760109
-
项目类别:
-
资助金额:$50.96万
-
财政年份:2001
-
负责人:Maria Jasin
-
依托单位:
海外基金