Role of HELLS chromatin remodeler in genome maintenance
Role of HELLS chromatin remodeler in genome maintenance
批准号:
10543683
负责人:
Wioletta Czaja
金额:
$2.39万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-01 至 2025-05-31
关键词:
AlkylationCellsChromatinChromosomal BreaksChromosomal RearrangementDNADNA AlkylationDNA DamageDNA MethylationDNA RepairDNA Repair PathwayDataDevelopmentDiagnosisDiseaseEventExhibitsFaceGametogenesisGeneticGenomeGenome StabilityGenomic InstabilityGenomicsGenotoxic StressHELLS geneHeterochromatinHumanImmune systemImmunologic Deficiency SyndromesLinkMaintenanceMediatingModelingMolecularMusMutationNeurosporaNeurospora crassaPathway interactionsPhenotypePlayProteinsRegulationResearchRoleToxic effectbasechromatin remodelingdisorder preventiongenomic locushuman diseaseimmunodeficiency-centromeric instability-facial anomalies syndromeinsightmutantnovel strategiesparent grantpreventrepairedresponse
中文摘要
项目摘要/摘要来自家长资助(1R01GM143428-01)
英文摘要
Project summary/abstract from parent grant (1R01GM143428-01)
Robust and tightly regulated DNA repair is critical to maintain genome stability and prevent disease
development. Eukaryotic DNA is packaged into chromatin that has a profound, yet not well understood regulatory
influence on DNA repair, replication, and genome maintenance. There is a fundamental gap in understanding
how DNA repair pathways are regulated and coordinated within structurally diverse chromatin, and across the
heterogeneous genomic landscape. The HELLS (Helicase Lymphoid Specific) is a poorly understood chromatin-
associated protein, with an emerging new role in genome maintenance. Mouse HELLS is essential for
gametogenesis and proper development of the immune system. Mutations in human HELLS cause severe
immunodeficiency syndrome ICF (Immunodeficiency Centromeric Instability Facial anomalies). Despite
substantial progress in understanding the molecular functions of the mammalian HELLS in DNA methylation and
chromatin remodeling, its role in DNA repair and genome maintenance is poorly understood and remains elusive.
The unresolved questions remain whether HELLS regulates multiple DNA repair pathways, and whether it has
specialized roles in the repair and maintenance of a distinct genomic loci or domains. We have established and
validated fungal model, Neurospora crassa to advance the fundamental understanding of HELLS-mediated
mechanisms of genome stability. Our studies reveal a new, previously unrecognized link between HELLS
proteins and cellular responses to DNA alkylation damage in fungal and human cells. We hypothesize that
HELLS protects cells form alkylation-induced toxicity and plays important roles in the repair and stability of the
constitutive heterochromatin domains. This hypothesis is founded based on a strong preliminary data in the
fungal model Neurospora and in human cells demonstrating that cells deficient in HELLS exhibit sensitivity to
DNA alkylation damage and are deficient in the repair of the constitutive heterochromatin. In addition, we
discovered that loss of fungal WDR76 protein in HELLS mutant cells leads to the synthetic rescue of the
alkylation sensitivity phenotype, implying that WDR76 acts as genetic suppressor of HELLS deficiency. In Aim 1
we will determine the role of fungal and human HELLS remodelers in the repair of alkylation DNA damage. In
Aim 2 we will define precise genomic and chromatin contexts that depend on HELLS for genome maintenance.
In Aim 3 we will determine the functional relationship between HELLS and WDR76, a WD40 protein implicated
in response to DNA alkylation. Successful completion of the proposed research will define HELLS-mediated
mechanisms of genome maintenance, and identify additional regulators and pathways cooperating with HELLS
in protecting the cells from detrimental consequences of genotoxic stress. These studies will provide important
insights into the origin of the disease-causing chromosomal rearrangements and breaks found in many human
diseases, including the ICF syndrome.
期刊论文(0)
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会议论文
Role of HELLS chromatin remodeler in genome maintenance
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批准号:10640990
-
项目类别:
-
资助金额:$31.27万
-
财政年份:2021
-
负责人:Wioletta Czaja
-
依托单位:
Role of HELLS chromatin remodeler in genome maintenance
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批准号:10792454
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项目类别:
-
资助金额:$32.49万
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财政年份:2021
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负责人:Wioletta Czaja
-
依托单位:
Role of HELLS chromatin remodeler in genome maintenance
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批准号:10629966
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项目类别:
-
资助金额:$1.21万
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财政年份:2021
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负责人:Wioletta Czaja
-
依托单位:
Role of HELLS chromatin remodeler in genome maintenance
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批准号:10279707
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项目类别:
-
资助金额:$34.63万
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财政年份:2021
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负责人:Wioletta Czaja
-
依托单位:
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