Regulation of translesion synthesis by the bacterial replisome

细菌复制体对跨损伤合成的调节

基本信息

  • 批准号:
    9064813
  • 负责人:
  • 金额:
    $ 32.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-05-15 至 2020-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): This project utilizes novel single-molecule approaches to elucidate the mechanisms by which the bacterial replisome regulates access of translesion polymerases to the replication fork and mediates translesion synthesis (TLS) across DNA lesions that block the replisome. Proper regulation of TLS is essential because TLS polymerases are significantly more error-prone than their replicative counterparts. Improper access of TLS polymerases to the replication fork is correlated with increased mutation rates in both prokaryotes and eukaryotes. Answers to fundamental mechanistic questions regarding how TLS occurs remain obscured in ensemble biochemical experiments due to the dynamic nature of TLS polymerase exchange. This project will exploit new developments in single-molecule manipulation and imaging to detect the many structural intermediates of the replisome that transiently arise during translesion synthesis. The three specific aims are: Aim 1) Determine how the processivity factor mediates polymerase exchange. Processive DNA synthesis by the polymerases of E. coli requires interactions with the bacterial processivity factor, ß. The ß clap is believed to be a loading platform for multiple polymerases but how polymerase-clamp interactions mediate polymerase trafficking at the replication fork remains unclear. This aim will utilize single-molecule approaches to characterize the kinetics of polymerase exchange and elucidate how ß-polymerase interactions facilitate switching. In parallel, single-molecule imaging of individual fluorescently labeled polymerases will directly quantify polymerase composition and conformation on ß. Aim 2) Determine how TLS polymerases associate with the replisome and carry out TLS. TLS is believed to occur either at moving replication forks through polymerase switching reactions or in ssDNA gaps generated by the replisome translocating past the lesion and repriming synthesis downstream. In this aim, single-molecule imaging of fluorescently labeled replisome components in vitro and in cells will be used to determine how TLS polymerases interact with a replisome that has collided with a leading strand lesion. Aim 3) Identify regulators of TLS within the SOS DNA damage response. Widespread DNA damage leads to induction of the SOS DNA damage response, which results in the transcriptional upregulation of over 40 gene products involved in DNA repair and TLS. On their own, SOS levels of TLS polymerases significantly inhibit replication, leading to suggestions that TLS polymerases may slow replication to allow DNA repair to occur. Yet, strains constitutively active for the SOS response appear to grow normally, indicating that SOS gene products play a role in regulating TLS polymerase access to the fork. We will determine how high concentrations of TLS polymerases remodel the replisome and work to understand how other SOS genes further regulate TLS.


项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Joseph J. Loparo其他文献

Single-Molecule Studies of a ParB Family Chromosome Segregation Protein from <em>Bacillussubtilis</em>
  • DOI:
    10.1016/j.bpj.2012.11.3236
  • 发表时间:
    2013-01-29
  • 期刊:
  • 影响因子:
  • 作者:
    Thomas G.W. Graham;Linda Song;Xindan Wang;Candice M. Etson;Antoine Van Oijen;David Z. Rudner;Joseph J. Loparo
  • 通讯作者:
    Joseph J. Loparo
Single-molecule Observations of Replisome Structure and Function
  • DOI:
    10.1016/j.bpj.2008.12.3655
  • 发表时间:
    2009-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Joseph J. Loparo;Samir M. Hamdan;Charles C. Richardson;M. van Antoine Oijen
  • 通讯作者:
    M. van Antoine Oijen
Visualizing the Dynamics of DNA Polymerase Exchange Through Simultaneous Single-Molecule Measurements of Replisome Composition and Function
  • DOI:
    10.1016/j.bpj.2010.12.262
  • 发表时间:
    2011-02-02
  • 期刊:
  • 影响因子:
  • 作者:
    Joseph J. Loparo
  • 通讯作者:
    Joseph J. Loparo
Measuring jumping during DNA target search
  • DOI:
    10.1016/j.bpj.2022.11.619
  • 发表时间:
    2023-02-10
  • 期刊:
  • 影响因子:
  • 作者:
    Allen C. Price;Van Nguyen;Joseph J. Loparo
  • 通讯作者:
    Joseph J. Loparo

Joseph J. Loparo的其他文献

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{{ truncateString('Joseph J. Loparo', 18)}}的其他基金

Molecular mechanisms of pathway choice in DNA double strand break repair
DNA双链断裂修复途径选择的分子机制
  • 批准号:
    10646302
  • 财政年份:
    2022
  • 资助金额:
    $ 32.63万
  • 项目类别:
Validating a potential interaction between error-prone polymerases and SSB as a therapeutic target for Mycobacterium tuberculosis
验证易错聚合酶和 SSB 之间潜在的相互作用作为结核分枝杆菌的治疗靶点
  • 批准号:
    10189804
  • 财政年份:
    2021
  • 资助金额:
    $ 32.63万
  • 项目类别:
Validating a potential interaction between error-prone polymerases and SSB as a therapeutic target for Mycobacterium tuberculosis
验证易错聚合酶和 SSB 之间潜在的相互作用作为结核分枝杆菌的治疗靶点
  • 批准号:
    10364697
  • 财政年份:
    2021
  • 资助金额:
    $ 32.63万
  • 项目类别:
Visualizing DNA break repair: single-molecule studies of non-homologous end joining
可视化 DNA 断裂修复:非同源末端连接的单分子研究
  • 批准号:
    10615061
  • 财政年份:
    2015
  • 资助金额:
    $ 32.63万
  • 项目类别:
Regulation of translesion synthesis by the bacterial replisome
细菌复制体对跨损伤合成的调节
  • 批准号:
    8858186
  • 财政年份:
    2015
  • 资助金额:
    $ 32.63万
  • 项目类别:
Visualizing DNA break repair: single-molecule studies of non-homologous end joining
可视化 DNA 断裂修复:非同源末端连接的单分子研究
  • 批准号:
    10384889
  • 财政年份:
    2015
  • 资助金额:
    $ 32.63万
  • 项目类别:
Visualizing DNA break repair: single-molecule studies of non-homologous end joining
可视化 DNA 断裂修复:非同源末端连接的单分子研究
  • 批准号:
    9885659
  • 财政年份:
    2015
  • 资助金额:
    $ 32.63万
  • 项目类别:
Visualizing DNA break repair: single-molecule studies of non-homologous end joining
可视化 DNA 断裂修复:非同源末端连接的单分子研究
  • 批准号:
    8939212
  • 财政年份:
    2015
  • 资助金额:
    $ 32.63万
  • 项目类别:
Regulation of translesion synthesis by the bacterial replisome
细菌复制体对跨损伤合成的调节
  • 批准号:
    10543767
  • 财政年份:
    2015
  • 资助金额:
    $ 32.63万
  • 项目类别:
Visualizing DNA break repair: single-molecule studies of non-homologous end joining
可视化 DNA 断裂修复:非同源末端连接的单分子研究
  • 批准号:
    10164800
  • 财政年份:
    2015
  • 资助金额:
    $ 32.63万
  • 项目类别:

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