Methyltransferase Contributions to Genomic Stability and Cancer
Methyltransferase Contributions to Genomic Stability and Cancer
批准号:
9130344
负责人:
WENDY KIMRYN RATHMELL
金额:
$44.09万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-01 至 2021-06-30
关键词:
AcuteAngiogenesis InhibitorsBiologicalBiologyChromatinChromosome SegregationChromosomesCouplingCytokinesisDNA DamageDNA Double Strand BreakDNA RepairDNA Sequence AlterationDataDefectDevelopmentDouble Strand Break RepairEnzymesEpigenetic ProcessEpithelialFrequenciesFutureGenesGenetic TranscriptionGenomeGenome StabilityGenomic InstabilityGenomicsHDAC6 geneHistone H3HistonesHumanInterventionLeftLinkLoss of HeterozygosityLysineMaintenanceMalignant NeoplasmsMeasurableMetastatic Renal Cell CancerMethylationMethyltransferaseMicrotubulesMitoticMitotic spindleModificationMono-SMutateMutationPathway interactionsPatternPhenotypePhosphoric Monoester HydrolasesPhosphotransferasesPreventionProcessPropertyReaderRenal Cell CarcinomaResistanceRoleSeriesSignal TransductionSourceStreamTestingTherapeuticTubulinTumor Suppressor Proteinsalpha Tubulinbasecancer cellchemical geneticschemotherapydesigneffective therapygene repairhistone methylationhistone methyltransferasein vivoinsightmicronucleusmutantnovelnovel therapeuticsopen dataprototyperepairedsegregationtargeted treatmenttooltraditional therapytumortumor progression
中文摘要
摘要
肾细胞癌(RCC)是研究表观遗传调节因子作为癌症主要驱动因素的原型
表型它也是一种值得注意的癌症,几乎没有有效的治疗选择,并且高度耐药。
许多传统疗法。最近在这种癌症中的一个发现是组蛋白SETD 2的高频突变,
甲基转移酶,是唯一负责将组蛋白H3赖氨酸36(H3 K36 me 3)
三甲基化标记活跃转录基因。我们的两个小组同时进行了一系列非常
与SETD 2甲基转移酶作为肿瘤抑制剂的新作用有关的令人兴奋的发现
基因组稳定性所必需的。首先,我们观察到染色质上H3 K36 me 3标记的缺失损害了
修复DNA双链断裂。这表明SETD 2的缺失导致了DNA修复缺陷,我们认为这是一种基因缺陷。
假设是由于错误定向的H3 K36 me 3“读者”,通常会引导DNA修复机制,
双链断裂,导致基因组不稳定。独立地说,我们最近有了令人兴奋的发现
一个重要的新的非组蛋白目标的SETD 2甲基转移酶:微管。这些数据显示
有丝分裂微管的赖氨酸40(K40 Me)上的α-微管蛋白的SETD 2甲基化是正常细胞增殖所必需的。
染色体分离和胞质分裂,为理解SETD 2的丢失如何贡献
基因组不稳定性和肾细胞癌进展的一个全新的方式。我们提出了一个多方面的
合作项目,以了解1)如何设置2作为一个组蛋白和微管甲基转移酶的功能
有助于基因组的稳定性和RCC的发展2)连接组蛋白甲基化的机制
缺陷的DNA双链断裂修复缺陷,和3)利用我们所知道的这种酶和
破坏生物学,以确定药理学工具化合物,我们将在体内测试,以探索关键
基因组维持的生物学特性或对未来靶向治疗有希望。
英文摘要
ABSTRACT
Renal cell carcinoma (RCC) is a prototype for the study of epigenetic regulators as major drivers of the cancer
phenotype. It is also a notable as a cancer with few effective treatment options, and high degree resistance to
many traditional therapies. One recent discovery in this cancer is high frequency mutation of SETD2, a histone
methyltransferase that is the sole enzyme responsible for placing the histone H3 lysine 36 (H3K36me3)
trimethylation mark on actively transcribed genes. Our two groups have in parallel made a series of very
exciting discoveries related to a new role for the SETD2 methyltransferase as a tumor suppressor
required for genomic stability. First, we observed that loss of the H3K36me3 mark on chromatin impairs
repair of DNA double strand breaks. This suggests that loss of SETD2 causes a DNA repair defect, which we
hypothesize is due to mis-directed H3K36me3 “readers” that would normally guide DNA repair machinery to
double strand breaks, resulting in genomic instability. Independently, we recently made the exciting discovery
of an important novel nonhistone target for the SETD2 methyltransferase: microtubules. These data show that
SETD2 methylation of α-tubulin on lysine 40 (K40Me) of mitotic microtubules is required for proper
chromosome segregation and cytokinesis, opening the door for understanding how loss of SETD2 contributes
to genomic instability and progression of RCC in a completely new way. We are proposing a multifaceted
collaborative project to understand 1) how SETD2 function as a histone and microtubule methyltransferase
contributes to genomic stability, and the development of RCC 2) the mechanism linking histone methylation
deficits to DNA double strand break repair deficiency, and 3) exploit what we know of this enzyme and the
biology of disruption to identify pharmacologic tool compounds, which we will test in vivo for exploring key
biological properties of genome maintenance or which hold promise for future targeted therapeutics.
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Career Enhancement Program
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批准号:10443617
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项目类别:
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资助金额:$9.56万
-
财政年份:2019
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负责人:WENDY KIMRYN RATHMELL
-
依托单位:
Career Enhancement Program
-
批准号:10700861
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项目类别:
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资助金额:$9.56万
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财政年份:2019
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Career Enhancement Program
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批准号:10218113
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项目类别:
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资助金额:$8.33万
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财政年份:2019
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
VIMORTP (Vanderbilt Integrated Molecular Oncology Research Training Program)
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批准号:10225434
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项目类别:
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资助金额:$18.76万
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财政年份:2018
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
VIMORTP (Vanderbilt Integrated Molecular Oncology Research Training Program)
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批准号:9981681
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项目类别:
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资助金额:$29.69万
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财政年份:2018
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
VIMORTP (Vanderbilt Integrated Molecular Oncology Research Training Program)
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批准号:10449242
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项目类别:
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资助金额:$29.24万
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财政年份:2018
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Methyltransferase Contributions to Genomic Stability and Cancer
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批准号:9518574
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项目类别:
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资助金额:$43.29万
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财政年份:2016
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Enhancing Translational Science via Prospective Investigation
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批准号:8692688
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项目类别:
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资助金额:$18.14万
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财政年份:2013
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Enhancing Translational Science via Prospective Investigation
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批准号:8883122
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项目类别:
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资助金额:$1.85万
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财政年份:2013
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Enhancing Translational Science via Prospective Investigation
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批准号:9181011
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项目类别:
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资助金额:$6.79万
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财政年份:2013
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Enhancing Translational Science via Prospective Investigation
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批准号:9249223
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项目类别:
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资助金额:$9.5万
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财政年份:2013
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Enhancing Translational Science via Prospective Investigation
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批准号:9102996
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项目类别:
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资助金额:$16.29万
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财政年份:2013
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Enhancing Translational Science via Prospective Investigation
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批准号:8581407
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项目类别:
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资助金额:$18.14万
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财政年份:2013
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Genetic Events in the Development of Renal Cell Carcinoma
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批准号:7655386
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项目类别:
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资助金额:$27.62万
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财政年份:2007
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Genetic Events in the Development of Renal Cell Carcinoma
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批准号:7457693
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项目类别:
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资助金额:$27.62万
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财政年份:2007
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Genetic Events in the Development of Renal Cell Carcinoma
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批准号:7197870
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项目类别:
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资助金额:$27.62万
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财政年份:2007
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Genetic Events in the Development of Renal Cell Carcinoma
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批准号:8072118
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项目类别:
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资助金额:$26.79万
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财政年份:2007
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
Genetic Events in the Development of Renal Cell Carcinoma
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批准号:7844972
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项目类别:
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资助金额:$27.62万
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财政年份:2007
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
DENDRITIC CELL VACCINE (MB-002) TO PATIENTS WITH METASTATIC RENAL CELL CARCINOMA
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批准号:7377501
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项目类别:
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资助金额:$0.02万
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财政年份:2005
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
CALGB 90206: INTERFERON ALFA-2B OR 2B PLUS BEVACIZUMAB IN RENAL CARCINOMA
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批准号:7377522
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项目类别:
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资助金额:$0.02万
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财政年份:2005
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负责人:WENDY KIMRYN RATHMELL
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依托单位:
海外基金