Mechanisms of heterochromatin replication
Mechanisms of heterochromatin replication
批准号:
10078281
负责人:
Marcus Smolka
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
项目状态:
已结题
起止时间:
2018-01-01 至 2022-12-31
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
中文摘要
项目总结
英文摘要
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.
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DOI:
10.1002/pmic.202200064
发表时间:
2022-08
期刊:
Proteomics
影响因子:
3.4
作者:
[]
通讯作者:
DOI:
10.1038/s41598-020-74939-4
发表时间:
2020-10-22
期刊:
Scientific reports
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
DOI:
10.1016/j.molcel.2021.04.006
发表时间:
2021-07-01
期刊:
Molecular cell
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:
Biochemical and biophysical research communications
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:
Bio-protocol
影响因子:
0.8
作者:
[Sanford,EthanJ, Smolka,MarcusB]
通讯作者:
Smolka,MarcusB
Signaling Mechanisms in Genome Maintenance
-
批准号:10374160
-
项目类别:
-
资助金额:$59.21万
-
财政年份:2021
-
负责人:Marcus Smolka
-
依托单位:
Signaling Mechanisms in Genome Maintenance
-
批准号:10597616
-
项目类别:
-
资助金额:$59.21万
-
财政年份:2021
-
负责人:Marcus Smolka
-
依托单位:
Signaling Mechanisms in Genome Maintenance (Equipment Supplement 2023)
-
批准号:10796621
-
项目类别:
-
资助金额:$18.74万
-
财政年份:2021
-
负责人:Marcus Smolka
-
依托单位:
Signaling Mechanisms in Genome Maintenance
-
批准号:10187261
-
项目类别:
-
资助金额:$34.28万
-
财政年份:2021
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负责人:Marcus Smolka
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依托单位:
Coordination of ATR Signaling for Genetic Quality Control, Silencing, and DNA Repair During Meiosis
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批准号:10413949
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项目类别:
-
资助金额:$41.93万
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财政年份:2018
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负责人:Marcus Smolka
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依托单位:
Coordination of ATR Signaling for Genetic Quality Control, Silencing, and DNA Repair During Meiosis
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批准号:10172957
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项目类别:
-
资助金额:$42.19万
-
财政年份:2018
-
负责人:Marcus Smolka
-
依托单位:
Cellular responses to DNA replication stress
-
批准号:9316211
-
项目类别:
-
资助金额:$33.2万
-
财政年份:2011
-
负责人:Marcus Smolka
-
依托单位:
Cellular responses to DNA replication stress
-
批准号:9923716
-
项目类别:
-
资助金额:$33.36万
-
财政年份:2011
-
负责人:Marcus Smolka
-
依托单位:
Cellular Responses to DNA Replication Stress
-
批准号:8535170
-
项目类别:
-
资助金额:$22.0万
-
财政年份:2011
-
负责人:Marcus Smolka
-
依托单位:
Cellular Responses to DNA Replication Stress
-
批准号:9354377
-
项目类别:
-
资助金额:$7.66万
-
财政年份:2011
-
负责人:Marcus Smolka
-
依托单位:
Cellular Responses to DNA Replication Stress
-
批准号:8194711
-
项目类别:
-
资助金额:$22.88万
-
财政年份:2011
-
负责人:Marcus Smolka
-
依托单位:
Cellular Responses to DNA Replication Stress
-
批准号:8917254
-
项目类别:
-
资助金额:$22.71万
-
财政年份:2011
-
负责人:Marcus Smolka
-
依托单位:
Cellular Responses to DNA Replication Stress
-
批准号:8721436
-
项目类别:
-
资助金额:$22.76万
-
财政年份:2011
-
负责人:Marcus Smolka
-
依托单位:
Cellular Responses to DNA Replication Stress
-
批准号:8323284
-
项目类别:
-
资助金额:$22.84万
-
财政年份:2011
-
负责人:Marcus Smolka
-
依托单位:
国内基金
海外基金
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