A Novel Process Safeguards Genome Integrity In The Mammalian Germ Line-Administrative Supplement to Support Undergraduate Summer Research Experiences

一种保护哺乳动物种系基因组完整性的新方法——支持本科生暑期研究经历的行政补充

基本信息

  • 批准号:
    10807301
  • 负责人:
  • 金额:
    $ 1.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-06-20 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Simple purine–pyrimidine (Pu/Py) repeats (PPRs) are known to form the left-handed, fragile Z-DNA structure. Such repeats are also known to be highly mutagenic, inducing large chromosomal deletions and rearrangements in the cells of higher organisms. The mutagenic effects of Z-DNA would be the most detrimental to a species if breaks occurred uncontrollably in the germ line and mutations occurring at unrepaired breaks were passed on to the next generation. We discovered a novel biological process in the mammalian germ line that controls Z-DNA structure at PPRs. Using the Zbtb43 mutant mouse genetic model and our transgenic mouse line that allows us to isolate germ cells, we found that a previously uncharacterized DNA binding protein, ZBTB43 remodels Z-DNA structure and protects from double-strand breaks in fetal male germ cells in vivo. By biochemical assays we found that ZBTB43 binds to PPR-rich DNA sites in the genome in vitro. ZBTB43 binding sites form Z-DNA and cause large genomic rearrangements in mammalian cells. By in vivo epigenome mapping we detected Z-DNA in mutant germ cells at the locations where ZBTB43 binding occurs in wild-type prospermatogonia. We hypothesize, therefore, that ZBTB43 safeguards genome integrity in the germ line by binding and eliminating Z-DNA at PPRs. In addition, we found that by eliminating Z-DNA, ZBTB43 promotes de novo methylation at PPRs during the time of global epigenetic remodeling. We propose to pursue the following aims, using a combination of genetic, cell biology, biochemistry, and epigenomic approaches. In Aim I, we will test the working hypothesis that ZBTB43 eliminates Z-DNA structure in vivo by directly binding to PPRs in fetal male germ cells. We will determine 1) the spatial and temporal changes of the Z-DNA structure in fetal male germ cells in the presence or absence of ZBTB43 protein in vivo; 2) the dependence of the Z-DNA remodeling process on the direct binding of ZBTB43 to the Z-DNA structure in vivo; and 3) the molecular requirements of ZBTB43 action on Z-DNA. In Aim 2, we will test the working hypothesis that ZBTB43 facilitates de novo DNA methylation in prospermatogonia indirectly by eliminating Z-DNA, thus revealing the sequences as substrates for de novo methyltransferases. We will map DNA methylation in the presence and absence of ZBTB43 during the epigenome remodeling process in fetal male germ cells. We will test whether de novo DNMTs methylate Z-DNA substrates in vitro. We will test whether ZBTB43 affects nucleosome occupancy at PPRs. In Aim 3, we will test the hypothesis that Z-DNA is mutagenic in the germ line and that ZBTB43 has evolved to manage that burden. We will map double- strand breaks in mutant fetal germ cells, test the anti-mutagenic effect of ZBTB43 in cell culture, and search for genomic rearrangements in sperm of Zbtb43 mutant males. By the end of the grant period, we will have identified and characterized the first example of how a DNA binding protein protects genome integrity and targets de novo DNA methylation by controlling Z-DNA structure in the mammalian germ line.
项目总结

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The remodeling of Z-DNA in the mammalian germ line.
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Piroska Edit Szabó其他文献

Piroska Edit Szabó的其他文献

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{{ truncateString('Piroska Edit Szabó', 18)}}的其他基金

A NOVEL PROCESS SAFEGUARDS GENOME INTEGRITY IN THE MAMMALIAN GERM LINE
保护哺乳动物生殖系基因组完整性的新工艺
  • 批准号:
    10445720
  • 财政年份:
    2022
  • 资助金额:
    $ 1.24万
  • 项目类别:
A NOVEL PROCESS SAFEGUARDS GENOME INTEGRITY IN THE MAMMALIAN GERM LINE
保护哺乳动物生殖系基因组完整性的新工艺
  • 批准号:
    10650391
  • 财政年份:
    2022
  • 资助金额:
    $ 1.24万
  • 项目类别:
Epigenetic effects if endocrine disruptors in fetal germ cells
胎儿生殖细胞中内分泌干扰物的表观遗传效应
  • 批准号:
    7645030
  • 财政年份:
    2006
  • 资助金额:
    $ 1.24万
  • 项目类别:
Epigenetic effects if endocrine disruptors in fetal germ cells
胎儿生殖细胞中内分泌干扰物的表观遗传效应
  • 批准号:
    7289321
  • 财政年份:
    2006
  • 资助金额:
    $ 1.24万
  • 项目类别:
Epigenetic effects if endocrine disruptors in fetal germ cells
胎儿生殖细胞中内分泌干扰物的表观遗传效应
  • 批准号:
    7448600
  • 财政年份:
    2006
  • 资助金额:
    $ 1.24万
  • 项目类别:
Epigenetic effects if endocrine disruptors in fetal germ cells
胎儿生殖细胞中内分泌干扰物的表观遗传效应
  • 批准号:
    7171695
  • 财政年份:
    2006
  • 资助金额:
    $ 1.24万
  • 项目类别:
Mechanisms of Genomic Imprinting
基因组印记机制
  • 批准号:
    7256615
  • 财政年份:
    2002
  • 资助金额:
    $ 1.24万
  • 项目类别:
Mechanisms of Genomic Imprinting
基因组印记机制
  • 批准号:
    7414514
  • 财政年份:
    2002
  • 资助金额:
    $ 1.24万
  • 项目类别:
Mechanisms of Genomic Imprinting
基因组印记机制
  • 批准号:
    7612019
  • 财政年份:
    2002
  • 资助金额:
    $ 1.24万
  • 项目类别:
Mechanism of Chromatin Insulator Imprinting
染色质绝缘体印迹机制
  • 批准号:
    6852647
  • 财政年份:
    2002
  • 资助金额:
    $ 1.24万
  • 项目类别:

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