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Mycobacterial non-homologous end-joi...

Stephanou, Nicolas Constantinos.

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Mycobacterial non-homologous end-joining: Molecular mechanisms and components of a novel DNA double strand break repair pathway.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Mycobacterial non-homologous end-joining: Molecular mechanisms and components of a novel DNA double strand break repair pathway./
Author:	Stephanou, Nicolas Constantinos.
Description:	177 p.
Notes:	Adviser: Michael Glickman.
Contained By:	Dissertation Abstracts International69-04B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3312041
ISBN:	9780549609858

Mycobacterial non-homologous end-joining: Molecular mechanisms and components of a novel DNA double strand break repair pathway.
Stephanou, Nicolas Constantinos.

Mycobacterial non-homologous end-joining: Molecular mechanisms and components of a novel DNA double strand break repair pathway. - 177 p.

Adviser: Michael Glickman.

Thesis (Ph.D.)--Weill Medical College of Cornell University, 2008.

The recent discovery of Ku and ATP-dependent ligase (LigD) homologues in a subset of bacteria led to the hypothesis that a non-homologous end-joining (NHEJ) DNA repair pathway exists in prokaryotes. Biochemical and genetic analysis pointed to a role of mycobacterial Ku and LigD in repairing linear plasmid in vivo. In order to probe the contribution of NHEJ in repairing chromosomal damage we constructed Mycobacterium smegmatis strains deficient in NHEJ and/or homologous recombination (HR) components and tested their sensitivity to various DNA damaging agents. We found that loss of Ku and LigD had no effect on sensitivity to UV radiation, methyl methanesulfonate, or quinolone antibiotics. NHEJ mutants grown to late stationary phase, thus limiting the availability of template DNA that would favor repair by HR, were more susceptible to killing by ionizing radiation than wt. In addition, NHEJ components were required for repair of I-SceI mediated chromosomal double-strand breaks, and in the absence of HR, the NHEJ pathway rapidly mutates the chromosomal break site.

ISBN: 9780549609858Subjects--Topical Terms:

1017730
Biology, Genetics.

Mycobacterial non-homologous end-joining: Molecular mechanisms and components of a novel DNA double strand break repair pathway.
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020 $a 9780549609858
035 $a (UMI)AAI3312041
035 $a AAI3312041
040 $a UMI $c UMI
100 1 $a Stephanou, Nicolas Constantinos. $3 1265029
245 1 0 $a Mycobacterial non-homologous end-joining: Molecular mechanisms and components of a novel DNA double strand break repair pathway.
300 $a 177 p.
500 $a Adviser: Michael Glickman.
500 $a Source: Dissertation Abstracts International, Volume: 69-04, Section: B, page: 2094.
502 $a Thesis (Ph.D.)--Weill Medical College of Cornell University, 2008.
520 $a The recent discovery of Ku and ATP-dependent ligase (LigD) homologues in a subset of bacteria led to the hypothesis that a non-homologous end-joining (NHEJ) DNA repair pathway exists in prokaryotes. Biochemical and genetic analysis pointed to a role of mycobacterial Ku and LigD in repairing linear plasmid in vivo. In order to probe the contribution of NHEJ in repairing chromosomal damage we constructed Mycobacterium smegmatis strains deficient in NHEJ and/or homologous recombination (HR) components and tested their sensitivity to various DNA damaging agents. We found that loss of Ku and LigD had no effect on sensitivity to UV radiation, methyl methanesulfonate, or quinolone antibiotics. NHEJ mutants grown to late stationary phase, thus limiting the availability of template DNA that would favor repair by HR, were more susceptible to killing by ionizing radiation than wt. In addition, NHEJ components were required for repair of I-SceI mediated chromosomal double-strand breaks, and in the absence of HR, the NHEJ pathway rapidly mutates the chromosomal break site.
520 $a In an effort to identify more components of the mycobacterial NHEJ system, we performed a genome-wide yeast two-hybrid screen using the M. tuberculosis Ku protein as bait. Multiple clones of the UvrD1 gene were found to interact with Ku. UvrD1 per se is a vigorous DNA-dependent ATPase, but a feeble DNA helicase. Interestingly, we found that Ku stimulates UvrD1 to catalyze efficient ATP-dependent unwinding of 3'-tailed DNAs. Ablation of UvrD1 sensitizes Mycobacterium smegmatis to killing by ultraviolet and ionizing radiation and to a single chromosomal break generated by I-SceI endonuclease, phenocopying Ku. These results point to a true functional interaction between UvrD1 and Ku, and highlight the potential for crosstalk between components of NHEJ and nucleotide excision repair pathways.
520 $a All these taken together provide clear evidence of an active prokaryotic NHEJ repair system that, like the eukaryotic counterpart, is highly mutagenic. The discovery of UvrD1 as a novel Ku interactor, taken with the phenotype of UvrD1 mutant in IR and I-SceI assays, point to a role of this NER component in repair of double strand breaks in collaboration with the mycobacterial NHEJ pathway.
590 $a School code: 0967.
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Biology, Microbiology. $3 1017734
650 4 $a Biology, Molecular. $3 1017719
690 $a 0307
690 $a 0369
690 $a 0410
710 2 $a Weill Medical College of Cornell University. $3 1021736
773 0 $t Dissertation Abstracts International $g 69-04B.
790 $a 0967
790 1 0 $a Glickman, Michael, $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3312041