Novel regulations of DNA damage repair
DNA损伤修复的新调控
基本信息
- 批准号:10087898
- 负责人:
- 金额:$ 43.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-16 至 2024-02-28
- 项目状态:已结题
- 来源:
- 关键词:Affinity ChromatographyBRCA mutationsBRCA1 geneBinding ProteinsCancer EtiologyCancer PatientCell DeathCell NucleusCellsChromatinClinicalCoupledDNADNA DamageDNA Double Strand BreakDNA RepairDNA Repair GeneDNA Repair PathwayDNA damage checkpointDNA lesionDataDefectDouble Strand Break RepairGenesGenomeGenomic InstabilityGoalsHumanImmunoglobulin Class SwitchingImmunoglobulin Switch RecombinationKnockout MiceLaboratoriesLeadMaintenanceMalignant NeoplasmsMalignant neoplasm of ovaryMass Spectrum AnalysisMediatingMolecularMutagenesisMutationNonhomologous DNA End JoiningOutcomePathway interactionsPlayPoly(ADP-ribose) PolymerasesProcessProteinsRadiationRegulationResistanceRoleSignal PathwaySiteSourceSun ExposureTumor Suppressor Proteinsbasebrca genecancer therapychemotherapeutic agentdriving forcegenome integrityhomologous recombinationin vivoinhibitor/antagonistmalignant breast neoplasmmutantneoplastic cellnovelp53-binding protein 1patient responserecombinational repairrecruitrepairedresistance mechanismresponsesenescencetargeted cancer therapytherapy resistanttreatment responsetumorigenesis
项目摘要
PROJECT SUMMARY
Defects in DNA damage response and DNA repair are the driving forces of genomic instability and
tumorigenesis. Gaining a better understanding of the pathways involved in DNA repair not only increases our
understanding of cancer etiology, but also provides new targets for cancer therapies. A key protein involved in
DNA repair and tumorigenesis is p53-binding protein 1, i.e. 53BP1.
My laboratory has been working on 53BP1 for many years. Our group was one of the first to demonstrate
the role of 53BP1 in DNA damage response. We established the first 53bp1 knockout (KO) mice; we also
revealed that 53BP1 is required for DNA repair and acts as a tumor suppressor in vivo. In addition, we
elucidated the regulation of 53BP1 after DNA damage. We and others demonstrated that the H2AX-dependent
DNA damage signaling pathway controls the recruitment and accumulation of 53BP1 at sites of DNA breaks.
However, 53BP1 can also localize to DNA damage sites in an H2AX-independent manner, although the
underlying mechanisms remain to be determined. Moreover, we showed that 53BP1 is critical for a particular
repair process called class-switch recombination, indicating that 53BP1 is involved in a special DNA repair
pathway that is distinctly different from the canonical nonhomologous end-joining pathway. Our recent studies
and those of others suggest that 53BP1 suppresses homologous recombination repair in BRCA1-deficient
cells, which is critically important for response to poly (ADP-ribose) polymerase inhibitor-based cancer
therapies. Together, these data highlight the importance of 53BP1 in counteracting homologous recombination
repair in response to DNA damage. In this proposal, we plan to focus on 53BP1 and elucidate at the molecular
level how 53BP1 is regulated after DNA damage and contributes to DNA repair and genome maintenance.
To further understand the regulation of 53BP1 localization and function at DNA damage sites, we recently
performed tandem affinity purification coupled with mass spectrometry analysis to identify proteins that would
specifically associate with a region of 53BP1, which is necessary and sufficient for its localization to DNA
damage sites. Surprisingly, we uncovered several novel 53BP1-binding proteins, including NUDT16,
NUDT16L1, and DEK. In this proposal, we will 1) further determine the roles of NUDT16L1 and NUDT16 in
53BP1 regulation and in the DNA damage response, and 2) elucidate the functional significance of DEK and
other newly discovered 53BP1-associated proteins in damage-induced 53BP1 localization, DNA repair, and
the maintenance of genomic integrity. These studies will help us understand the key components that act
upstream of 53BP1 and function together with 53BP1 in DNA repair and genome maintenance.
项目摘要
DNA损伤反应和DNA修复的缺陷是基因组不稳定性的驱动力,
肿瘤发生更好地了解DNA修复中涉及的途径不仅可以增加我们的免疫力,
这不仅有助于了解癌症病因,而且还为癌症治疗提供了新的靶点。参与其中的关键蛋白质
DNA修复和肿瘤发生是p53结合蛋白1,即53 BP 1。
我的实验室多年来一直在研究53 BP 1。我们是第一批证明
53 BP 1在DNA损伤反应中的作用我们建立了第一个53 bp 1敲除(KO)小鼠;我们还
揭示了53 BP 1是DNA修复所必需的,并在体内充当肿瘤抑制因子。另外我们
阐明了53 BP 1在DNA损伤后的调节作用。我们和其他人证明了H2 AX依赖性
DNA损伤信号通路控制53 BP 1在DNA断裂位点的募集和积累。
然而,53 BP 1也可以以不依赖H2 AX的方式定位于DNA损伤位点,尽管53 BP 1的表达与H2 AX无关。
根本机制仍有待确定。此外,我们发现53 BP 1对一个特定的
这一修复过程被称为类别转换重组,表明53 BP 1参与了一种特殊的DNA修复
这是明显不同于典型的非同源末端连接途径的途径。我们最近的研究
和其他人的结果表明,53 BP 1抑制BRCA 1缺陷的同源重组修复,
细胞,这是至关重要的反应聚(ADP-核糖)聚合酶的癌症为基础的
治疗总之,这些数据突出了53 BP 1在抵消同源重组中的重要性
修复DNA损伤。在本提案中,我们计划重点关注53 BP 1并从分子水平进行阐明
水平53 BP 1是如何在DNA损伤后调节,并有助于DNA修复和基因组维护。
为了进一步了解53 BP 1在DNA损伤位点的定位和功能调节,我们最近
进行串联亲和纯化,结合质谱分析,以鉴定
特异性地与53 BP 1区域相关,该区域对于其定位于DNA是必需和充分的
损伤部位。令人惊讶的是,我们发现了几种新的53 BP 1结合蛋白,包括NUDT 16,
NUDT 16 L1和DEK.在本提案中,我们将1)进一步确定NUDT 16 L1和NUDT 16在以下方面的作用:
53 BP 1调控和DNA损伤反应,2)阐明DEK和
其他新发现的53 BP 1相关蛋白在损伤诱导的53 BP 1定位,DNA修复,
保持基因组的完整性。这些研究将帮助我们了解
53 BP 1的上游,并与53 BP 1一起在DNA修复和基因组维护中发挥作用。
项目成果
期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis.
- DOI:10.15252/embj.2021107776
- 发表时间:2021-09-01
- 期刊:
- 影响因子:0
- 作者:Chen Z;Wang C;Feng X;Nie L;Tang M;Zhang H;Xiong Y;Swisher SK;Srivastava M;Chen J
- 通讯作者:Chen J
Histone chaperone ASF1 acts with RIF1 to promote DNA end joining in BRCA1-deficient cells.
- DOI:10.1016/j.jbc.2022.101979
- 发表时间:2022-06
- 期刊:
- 影响因子:4.8
- 作者:Tang, Mengfan;Chen, Zhen;Wang, Chao;Feng, Xu;Lee, Namsoo;Huang, Min;Zhang, Huimin;Li, Siting;Xiong, Yun;Chen, Junjie
- 通讯作者:Chen, Junjie
Biological and clinical aspects of HPV-related cancers.
- DOI:10.20892/j.issn.2095-3941.2020.0370
- 发表时间:2020-11-15
- 期刊:
- 影响因子:5.5
- 作者:Szymonowicz KA;Chen J
- 通讯作者:Chen J
Identification and characterization of BEND2 as a key regulator of meiosis during mouse spermatogenesis.
- DOI:10.1126/sciadv.abn1606
- 发表时间:2022-05-27
- 期刊:
- 影响因子:13.6
- 作者:
- 通讯作者:
Integrated screens uncover a cell surface tumor suppressor gene KIRREL involved in Hippo pathway.
- DOI:10.1073/pnas.2121779119
- 发表时间:2022-06-21
- 期刊:
- 影响因子:11.1
- 作者:
- 通讯作者:
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Junjie Chen其他文献
Junjie Chen的其他文献
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{{ truncateString('Junjie Chen', 18)}}的其他基金
Deciphering pathways involved in topoisomerase II turnover
破译拓扑异构酶 II 周转涉及的途径
- 批准号:
10552113 - 财政年份:2023
- 资助金额:
$ 43.64万 - 项目类别:
Elucidating mechanisms underlying replication checkpoint control
阐明复制检查点控制的底层机制
- 批准号:
10620981 - 财政年份:2023
- 资助金额:
$ 43.64万 - 项目类别:
Exploring DNA damage response pathways as targets for cancer therapy
探索 DNA 损伤反应途径作为癌症治疗的目标
- 批准号:
10515484 - 财政年份:2022
- 资助金额:
$ 43.64万 - 项目类别:
Define redundant functions of H2AX and NBS1 in DNA repair
定义DNA修复中H2AX和NBS1的冗余功能
- 批准号:
10311996 - 财政年份:2017
- 资助金额:
$ 43.64万 - 项目类别:
Project 4: Coordinating Nucleolytic Pathways During Crosslink Repair
项目 4:在交联修复过程中协调溶核途径
- 批准号:
9148677 - 财政年份:2017
- 资助金额:
$ 43.64万 - 项目类别:
Define redundant functions of H2AX and NBS1 in DNA repair
定义DNA修复中H2AX和NBS1的冗余功能
- 批准号:
9206732 - 财政年份:2017
- 资助金额:
$ 43.64万 - 项目类别:
Define redundant functions of H2AX and NBS1 in DNA repair
定义DNA修复中H2AX和NBS1的冗余功能
- 批准号:
10053713 - 财政年份:2017
- 资助金额:
$ 43.64万 - 项目类别:
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