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The pathways and outcomes of mycobac...

Weill Medical College of Cornell University.

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The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends./
Author:	Aniukwu, Jideofor Flint.
Description:	133 p.
Notes:	Advisers: Stewart Shuman; Michael Glickman.
Contained By:	Dissertation Abstracts International69-04B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3312034
ISBN:	9780549609766

The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends.
Aniukwu, Jideofor Flint.

The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends. - 133 p.

Advisers: Stewart Shuman; Michael Glickman.

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

Mycobacteria can repair DNA double-strand breaks (DSBs) via a nonhomologous end joining (NHEJ) system that includes a dedicated DNA ligase (LigD) and the DNA end-binding protein Ku. Here an improved plasmid-based NHEJ assay and a collection of M. smegmatis strains bearing deletions or mutations in Ku or the DNA ligases are exploited to interrogate the contributions of LigD's three catalytic activities (polymerase, ligase and 3' phosphoesterase) and structural domains (POL, LIG and PE) to the efficiency and molecular outcomes of NHEJ in vivo. By analyzing in parallel the repair of blunt, 5' overhang, and 3' overhang DSBs, a novel end joining pathway was discovered specific to breaks with 3' overhangs that is Ku- and LigD-independent and perfectly faithful. This 3' overhang NHEJ pathway is independent of ligases B and C; it can be surmised that it relies on NAD+-dependent LigA, the essential replicative ligase. Efficient repair of blunt and 5' overhang DSBs depends stringently on Ku and the LigD POL domain, but not on the LigD polymerase activity, which mainly serves to promote NHEJ infidelity. The lack of an effect of PE-inactivating LigD mutations on NHEJ outcomes, especially the balance between deletions and insertions at blunt or 5' overhang breaks, argues against LigD being the catalyst of deletion formation. Ligase-inactivating LigD mutations (or deletion of the LIG domain) have modest impact on the efficiency of blunt and 5' overhang DSB repair, because the strand sealing activity can be provided in trans by one of the other resident ATP-dependent ligases (likely LigC). Reliance on the backup ligase is accompanied by a drastic loss of fidelity during blunt end and 5' overhang DSB repair. It can be concluded that the mechanisms of mycobacterial NHEJ are many and the outcomes depend on the initial structures of the DSBs and the available ensemble of end-processing and end-sealing components, which are not limited to Ku and LigD.

ISBN: 9780549609766Subjects--Topical Terms:

1017730
Biology, Genetics.

The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends.
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020 $a 9780549609766
035 $a (UMI)AAI3312034
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100 1 $a Aniukwu, Jideofor Flint. $3 1021737
245 1 4 $a The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends.
300 $a 133 p.
500 $a Advisers: Stewart Shuman; Michael Glickman.
500 $a Source: Dissertation Abstracts International, Volume: 69-04, Section: B, page: 2098.
502 $a Thesis (Ph.D.)--Weill Medical College of Cornell University, 2008.
520 $a Mycobacteria can repair DNA double-strand breaks (DSBs) via a nonhomologous end joining (NHEJ) system that includes a dedicated DNA ligase (LigD) and the DNA end-binding protein Ku. Here an improved plasmid-based NHEJ assay and a collection of M. smegmatis strains bearing deletions or mutations in Ku or the DNA ligases are exploited to interrogate the contributions of LigD's three catalytic activities (polymerase, ligase and 3' phosphoesterase) and structural domains (POL, LIG and PE) to the efficiency and molecular outcomes of NHEJ in vivo. By analyzing in parallel the repair of blunt, 5' overhang, and 3' overhang DSBs, a novel end joining pathway was discovered specific to breaks with 3' overhangs that is Ku- and LigD-independent and perfectly faithful. This 3' overhang NHEJ pathway is independent of ligases B and C; it can be surmised that it relies on NAD+-dependent LigA, the essential replicative ligase. Efficient repair of blunt and 5' overhang DSBs depends stringently on Ku and the LigD POL domain, but not on the LigD polymerase activity, which mainly serves to promote NHEJ infidelity. The lack of an effect of PE-inactivating LigD mutations on NHEJ outcomes, especially the balance between deletions and insertions at blunt or 5' overhang breaks, argues against LigD being the catalyst of deletion formation. Ligase-inactivating LigD mutations (or deletion of the LIG domain) have modest impact on the efficiency of blunt and 5' overhang DSB repair, because the strand sealing activity can be provided in trans by one of the other resident ATP-dependent ligases (likely LigC). Reliance on the backup ligase is accompanied by a drastic loss of fidelity during blunt end and 5' overhang DSB repair. It can be concluded that the mechanisms of mycobacterial NHEJ are many and the outcomes depend on the initial structures of the DSBs and the available ensemble of end-processing and end-sealing components, which are not limited to Ku and LigD.
590 $a School code: 0967.
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650 4 $a Biology, Microbiology. $3 1017734
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790 1 0 $a Shuman, Stewart, $e advisor
791 $a Ph.D.
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