Mechanisms of heterochromatin replication
异染色质复制机制
基本信息
- 批准号:10078281
- 负责人:
- 金额:$ 30.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-01-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcetyltransferaseBindingBiochemicalBiologicalCell ProliferationCell physiologyCellsCentromereChromatinComplexCouplesCouplingDNA DamageDNA biosynthesisDNA lesionGenomeGenomic InstabilityGenomic approachGenomicsHAT1 geneHeterochromatinHistone AcetylationHistonesHumanImaging TechniquesKnowledgeLinkLocationMaintenanceMalignant NeoplasmsMalignant neoplasm of ovaryMeasuresMediator of activation proteinMethylationMethyltransferaseMitosisMolecularMonitorMultiple MyelomaMutationNatureProliferatingProtein FamilyProteomicsRegulationReplication InitiationRoleS PhaseS-AdenosylmethionineSatellite DNASiteSomatic CellSystemTechniquesTestingTherapeuticTimecancer cellcancer typedensityexperimental studygenome integritygenomic locushistone acetyltransferaseinsightmembernew therapeutic targetnoveloverexpressionpreventtelomerevirtual
项目摘要
PROJECT SUMMARY
Heterochromatic domains, such as centromeres, telomeres and other satellite DNA, pose a major challenge for
DNA replication. Compacted chromatin is thought to inhibit replication initiation and obstruct progression of the
replication machinery. Not surprisingly, recent analyses of various somatic and cancer cells have revealed that
repressive chromatin is associated with regions of late replication and high mutation density. Little, however, is
known about the molecular mechanisms that control and facilitate DNA replication at heterochromatic domains.
Of importance, cancer cells may harness these mechanisms to facilitate heterochromatin replication and
sustain their increased proliferative demands. For example, overexpression of KDM4A/JMJD2, a demethylase
that removes the heterochromatic mark H3K9 tri-methylation, enables chromatin de-compaction and
accelerated replication in ovarian cancers. Strikingly, KDM4A overexpression also resulted in copy gain of
specific genomic loci often amplified in ovarian cancers and multiple myeloma, further strengthening the link
between de-regulated heterochromatin replication and genomic instability. These observations highlight the
need to elucidate the mechanisms required for proper heterochromatin replication so as to understand
fundamental aspects of genome maintenance and the control of cell proliferation.
This proposal is centered on METTL13 (Methyltransferase-like 13), a member of a poorly understood
family of proteins containing putative SAM (S-adenosylmethionine)-binding domains. While METTL13 was
found amplified and overexpressed in cancers, virtually nothing was previously known about its cellular
functions. Preliminary results presented here provide the first insights on how METTL13 sustains cell
proliferation, revealing crucial roles in DNA replication and chromatin dynamics. More specifically, we find that
METTL13 is a novel key mediator of heterochromatin replication that is particularly important for replication of
centromeres. To the best of our knowledge this is the first described regulator of human centromere
replication timing. This proposal will combine cutting edge genomic and proteomic techniques with
biochemical and cell biological approaches to dissect the action of METTL13 and establish its role in
controlling chromatin dynamics, DNA replication and genome integrity. Generated results will reveal a
fundamental mechanism of heterochromatin replication and replication timing control, and will establish novel
drug targets for modulating chromatin dynamics and the proliferative capacity of cancer cells.
项目摘要
异染色质结构域,如着丝粒、端粒和其他卫星DNA,对人类的遗传学构成了重大挑战。
DNA复制。致密的染色质被认为抑制复制起始并阻碍细胞增殖的进展。
复制机器毫不奇怪,最近对各种体细胞和癌细胞的分析表明,
抑制性染色质与晚期复制和高突变密度的区域相关。然而,
已知控制和促进异染色质域DNA复制的分子机制。
重要的是,癌细胞可以利用这些机制来促进异染色质复制,
以满足其日益增长的需求。例如,KDM 4A/JMJD 2,一种脱甲基酶,
去除异染色质标记H3 K9三甲基化,使染色质去致密化,
卵巢癌的加速复制。引人注目的是,KDM 4A过表达也导致了KDM 4A基因的拷贝增加。
在卵巢癌和多发性骨髓瘤中经常扩增的特定基因组位点,进一步加强了这种联系,
异染色质复制失调和基因组不稳定性之间的联系这些观察突出了
需要阐明异染色质复制所需的机制,以了解
基因组维持和细胞增殖控制的基本方面。
该建议以胃L13(甲基转移酶样13)为中心,其是一个知之甚少的
含有假定SAM(S-腺苷甲硫氨酸)结合结构域的蛋白质家族。而L13则是一种
在癌症中发现了扩增和过度表达,以前对它的细胞功能几乎一无所知。
功能协调发展的本文提供的初步结果提供了关于胃L13如何维持细胞生长的第一个见解。
增殖,揭示了DNA复制和染色质动力学的关键作用。更具体地说,我们发现,
胃L13是异染色质复制的一种新的关键介质,对复制
着丝粒据我们所知,这是第一个被描述的人类着丝粒调节器
复制定时。该提案将联合收割机结合尖端的基因组学和蛋白质组学技术,
生物化学和细胞生物学方法来剖析胃L13的作用,并确定其在
控制染色质动力学、DNA复制和基因组完整性。生成的结果将显示
异染色质复制和复制时序控制的基本机制,并将建立新的
用于调节染色质动力学和癌细胞增殖能力的药物靶标。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A field guide to the proteomics of post-translational modifications in DNA repair.
- DOI:10.1002/pmic.202200064
- 发表时间:2022-08
- 期刊:
- 影响因子:3.4
- 作者:
- 通讯作者:
Maximized quantitative phosphoproteomics allows high confidence dissection of the DNA damage signaling network.
- DOI:10.1038/s41598-020-74939-4
- 发表时间:2020-10-22
- 期刊:
- 影响因子:4.6
- 作者:Faca VM;Sanford EJ;Tieu J;Comstock W;Gupta S;Marshall S;Yu H;Smolka MB
- 通讯作者:Smolka MB
Checkpoint-mediated DNA polymerase ε exonuclease activity curbing counteracts resection-driven fork collapse.
- DOI:10.1016/j.molcel.2021.04.006
- 发表时间:2021-07-01
- 期刊:
- 影响因子:16
- 作者:Pellicanò G;Al Mamun M;Jurado-Santiago D;Villa-Hernández S;Yin X;Giannattasio M;Lanz MC;Smolka MB;Yeeles J;Shirahige K;García-Díaz M;Bermejo R
- 通讯作者:Bermejo R
Characterization of an anti-FLAG antibody binding protein in V. cholerae.
霍乱弧菌中抗 FLAG 抗体结合蛋白的表征。
- DOI:10.1016/j.bbrc.2020.05.169
- 发表时间:2020
- 期刊:
- 影响因子:3.1
- 作者:Shin,Jung-Ho;Lanz,Michael;Smolka,MarcusB;Dörr,Tobias
- 通讯作者:Dörr,Tobias
Fe-NTA Microcolumn Purification of Phosphopeptides from Immunoprecipitation (IP) Eluates for Mass Spectrometry Analysis.
Fe-NTA 微柱纯化免疫沉淀 (IP) 洗脱液中的磷酸肽,用于质谱分析。
- DOI:10.21769/bioprotoc.4113
- 发表时间:2021
- 期刊:
- 影响因子:0.8
- 作者:Sanford,EthanJ;Smolka,MarcusB
- 通讯作者:Smolka,MarcusB
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Marcus Smolka其他文献
Marcus Smolka的其他文献
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{{ truncateString('Marcus Smolka', 18)}}的其他基金
Signaling Mechanisms in Genome Maintenance (Equipment Supplement 2023)
基因组维护中的信号机制(设备增刊 2023)
- 批准号:
10796621 - 财政年份:2021
- 资助金额:
$ 30.11万 - 项目类别:
Coordination of ATR Signaling for Genetic Quality Control, Silencing, and DNA Repair During Meiosis
减数分裂期间遗传质量控制、沉默和 DNA 修复的 ATR 信号协调
- 批准号:
10413949 - 财政年份:2018
- 资助金额:
$ 30.11万 - 项目类别:
Coordination of ATR Signaling for Genetic Quality Control, Silencing, and DNA Repair During Meiosis
减数分裂期间遗传质量控制、沉默和 DNA 修复的 ATR 信号协调
- 批准号:
10172957 - 财政年份:2018
- 资助金额:
$ 30.11万 - 项目类别:
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