Impact of ATR's role in translesion synthesis on prevention of DNA damage induced mutagenesis and chromosomal instability
Impact of ATR's role in translesion synthesis on prevention of DNA damage induced mutagenesis and chromosomal instability
批准号:
10634852
负责人:
SATYA PRAKASH
金额:
$32.0万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-03-22 至 2027-01-31
关键词:
Active SitesAgingApoptoticBRCT DomainBase Excision RepairsBase PairingBiochemicalCarcinogensCell DeathCell physiologyCellsChromosomal InstabilityChromosome abnormalityComplexDNADNA AdductionDNA AdductsDNA DamageDNA biosynthesisDNA lesionDNA replication forkDNA-Directed DNA PolymeraseGeneticGenetic studyGenome StabilityGenomic InstabilityGenomicsGrowthHomeostasisHumanImpairmentKineticsLesionLinkMediatingMolecular ConformationMutagenesisMutationNucleotide Excision RepairNucleotidesPathway interactionsPhosphorylationPhosphotransferasesPlayPolymerasePreventionProcessPurinesPyrimidine DimersReactionRoleSeckel syndromeSiteSpecificityStructureUV inducedUbiquitinationadductadverse outcomeirradiationnovelnucleotide metabolismpollutantpreventreconstitutionreplication stressrestraintscaffoldtumorigenesisubiquitin ligaseultraviolet lesions
中文摘要
翻译合成(TLS) DNA聚合酶(pol)通过DNA损伤促进复制。生物化学,
英文摘要
Translesion synthesis (TLS) DNA polymerases (Pols) promote replication through DNA lesions. Biochemical,
structural, and genetic studies have indicated that TLS Pols play highly specialized roles in replicating through
DNA lesions. Although there is a great deal of information on the structure and function of TLS Pols, and on the
multiplicity of pathways that mediate predominantly error-free TLS and which utilize the action of one TLS Pol or
the sequential action of two Pols, there is no information on how these TLS processes are regulated. Based
upon the evidence we provide here, we propose a role for ATR kinase in normal human cells in (a) promoting
predominantly error-free TLS via multiple pathways; (b) promoting TLS in conjunction with the replisome stalled
and stabilized at DNA lesion sites; and (c) in coordinating TLS by the sequential action of two Pols in which one
Pol inserts a nucleotide opposite the DNA lesion and another Pol extends synthesis therefrom. In Aim 1, we will
carry out studies to establish that unlike in ATR proficient cells where TLS operates via multiple, predominantly
error-free pathways, TLS in ATR deficient cells operates via a single highly error-prone pathway. In Aim 2, to
establish that ATR promotes proficient TLS dependent replication through DNA lesions in conjunction with the
replisome at replication forks (RFs) stalled at DNA lesion sites, we will analyze the ways in which TLS in ATR
deficient cells differs from that in ATR proficient cells. For these studies, we will: (a) determine the extent by
which RF progression through UV lesions is inhibited in ATR deficient cells compared to that in ATR proficient
cells; (b) determine that whereas TLS operates in conjunction with replisome in ATR proficient cells, the
replisome disassembles in ATR deficient cells; subsequently, TLS occurs in gaps, requires PrimPol for initiating
DNA synthesis, and CRL4Cdt2 ubiquitin ligase for PCNA ubiquitination; (c) determine whether accumulation of
Pol at cyclobutane pyrimidine dimers (CPDs) occurs with slower kinetics and at reduced levels in ATR deficient
cells compared to that in ATR proficient cells; and (d) determine whether RF collapse resulting from replisome
disassembly at DNA lesion sites in ATR deficient cells confers a large elevation in chromosomal aberrations and
apoptotic cell death. In Aim 3, we will analyze the role of ATR mediated phosphorylation of TLS Pols in the
formation of a TLS Pol ensemble so that the two different steps of TLS dependent upon two Pols occur in one
physical entity, rather than independently.
The evidence that in contrast to ATR proficient cells, TLS dependent replication through DNA lesions in ATR
deficient cells operates in highly mutagenic ways, occurs in gaps, is conducted differently and much less
efficiently, and that chromosomal instability and apoptotic cell death are highly elevated in the absence of ATR,
will be important for establishing that by restraining DNA damage induced mutagenesis, chromosomal instability,
and apoptotic cells death, ATR’s role in TLS would contribute to genome stability and cellular homeostasis.
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会议论文
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Role of human DNA polymerase kappa in replicative bypass of DNA lesions
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Role of human DNA polymerase kappa in replicative bypass of DNA lesions
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依托单位:
Role of Rev1 in error-free replication of DNA damage and in mutation prevention
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资助金额:$43.19万
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财政年份:2008
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依托单位:
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资助金额:$43.19万
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财政年份:2008
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负责人:SATYA PRAKASH
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依托单位:
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批准号:7462040
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Hoogsteen base pairing in human DNA polymerase iota
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海外基金