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.advisor | Turchi, John J. | |
dc.contributor.author | Woods, Derek S. | |
dc.contributor.other | Harrington, Maureen A. | |
dc.contributor.other | Malkova, Anna L. | |
dc.contributor.other | Takagi, Yuichiro | |
dc.date.accessioned | 2014-07-11T20:33:37Z | |
dc.date.available | 2014-07-11T20:33:37Z | |
dc.date.issued | 2013-11 | |
dc.degree.date | 2013 | en_US |
dc.degree.discipline | Department of Biochemistry & Molecular Biology | en |
dc.degree.grantor | Indiana University | en_US |
dc.degree.level | Ph.D. | en_US |
dc.description | Indiana University-Purdue University Indianapolis (IUPUI) | en_US |
dc.description.abstract | In 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.uri | https://hdl.handle.net/1805/4665 | |
dc.identifier.uri | http://dx.doi.org/10.7912/C2/1851 | |
dc.language.iso | en_US | en_US |
dc.subject | DNA Repair, | en_US |
dc.subject | NHEJ | en_US |
dc.subject | DNA-PK | en_US |
dc.subject | Ku70/80 | en_US |
dc.subject | Ku80 Carboxy Terminus | en_US |
dc.subject.lcsh | DNA -- Research -- Methodology | en_US |
dc.subject.lcsh | DNA-protein interactions | en_US |
dc.subject.lcsh | Protein-protein interactions | en_US |
dc.subject.lcsh | DNA -- Synthesis | en_US |
dc.subject.lcsh | Enzymes -- Analysis | en_US |
dc.subject.lcsh | Protein kinases -- Research -- Evaluation | en_US |
dc.subject.lcsh | DNA repair | en_US |
dc.subject.lcsh | DNA damage | en_US |
dc.subject.lcsh | DNA-binding proteins | en_US |
dc.subject.lcsh | Cellular control mechanisms | en_US |
dc.subject.lcsh | Nucleotide sequence | en_US |
dc.subject.lcsh | Mutagenesis | en_US |
dc.subject.lcsh | Biochemical genetics | en_US |
dc.title | 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 | en_US |
dc.type | Thesis | en |