The influence of the Ku80 carboxy-terminus on activation of the DNA-dependent protein kinase and DNA repair is dependent on the structure of DNA cofactors

dc.contributor.advisorTurchi, John J.
dc.contributor.authorWoods, Derek S.
dc.contributor.otherHarrington, Maureen A.
dc.contributor.otherMalkova, Anna L.
dc.contributor.otherTakagi, Yuichiro
dc.date.accessioned2014-07-11T20:33:37Z
dc.date.available2014-07-11T20:33:37Z
dc.date.issued2013-11
dc.degree.date2013en_US
dc.degree.disciplineDepartment of Biochemistry & Molecular Biologyen
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractIn mammalian cells DNA double strand breaks (DSBs) are highly variable with respect to sequence and structure all of which are recognized by the DNA- dependent protein kinase (DNA-PK), a critical component for the resolution of these breaks. Previously studies have shown that DNA-PK does not respond the same way to all DSBs but how DNA-PK senses differences in DNA substrate sequence and structure is unknown. Here we explore the enzymatic mechanism by which DNA-PK is activated by various DNA substrates. We provide evidence that recognition of DNA structural variations occur through distinct protein-protein interactions between the carboxy terminal (C-terminal) region of Ku80 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Discrimination of terminal DNA sequences, on the other hand, occurs independently of Ku 80 C-terminal interactions and results exclusively from DNA-PKcs interactions with the DNA. We also show that sequence differences in DNA termini can drastically influence DNA repair through altered DNA-PK activation. Our results indicate that even subtle differences in DNA substrates influence DNA-PK activation and ultimately Non-homologous End Joining (NHEJ) efficiency.en_US
dc.identifier.urihttps://hdl.handle.net/1805/4665
dc.identifier.urihttp://dx.doi.org/10.7912/C2/1851
dc.language.isoen_USen_US
dc.subjectDNA Repair,en_US
dc.subjectNHEJen_US
dc.subjectDNA-PKen_US
dc.subjectKu70/80en_US
dc.subjectKu80 Carboxy Terminusen_US
dc.subject.lcshDNA -- Research -- Methodologyen_US
dc.subject.lcshDNA-protein interactionsen_US
dc.subject.lcshProtein-protein interactionsen_US
dc.subject.lcshDNA -- Synthesisen_US
dc.subject.lcshEnzymes -- Analysisen_US
dc.subject.lcshProtein kinases -- Research -- Evaluationen_US
dc.subject.lcshDNA repairen_US
dc.subject.lcshDNA damageen_US
dc.subject.lcshDNA-binding proteinsen_US
dc.subject.lcshCellular control mechanismsen_US
dc.subject.lcshNucleotide sequenceen_US
dc.subject.lcshMutagenesisen_US
dc.subject.lcshBiochemical geneticsen_US
dc.titleThe influence of the Ku80 carboxy-terminus on activation of the DNA-dependent protein kinase and DNA repair is dependent on the structure of DNA cofactorsen_US
dc.typeThesisen
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