The Gam protein of bacteriophage Mu is an orthologue of eukaryotic Ku

Fagagna, Fabrizio d’Adda di; Weller, Geoffrey R.; Doherty, Aidan J.; Jackson, Stephen

doi:10.1038/sj.embor.embor709

Cited by 57 publications

(57 citation statements)

References 25 publications

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“…We speculate that the mycobacteriophage-encoded Ku might be deposited at the ends of the linear phage genome during DNA encapsidation, where it is poised to direct sealing of the injected phage DNA down the LigD-dependent pathway during the next round of infection. Mycobacteriophage Ku, in common with the Ku-like Gam protein of bacteriophage Mu (d'Adda di Fagagna et al 2003), is a homodimer that binds to linear DNA ends and protects them from exonucleolytic digestion (Pitcher et al 2006). …”

Section: Discussionmentioning

confidence: 99%

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

Aniukwu¹,

Glickman²,

Shuman³

2008

Genes Dev.

107

179

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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 we exploit an improved plasmid-based NHEJ assay and a collection of Mycobacterium smegmatis strains bearing deletions or mutations in Ku or the DNA ligases 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, we discovered a novel end-joining pathway 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; we surmise that it relies on NAD + -dependent LigA, the essential replicative ligase. We find that 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 a 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. We conclude 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.[Keywords: Double-strand breaks; DNA ligase; Ku; end-joining; mutation] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionmentioning

confidence: 99%

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

Aniukwu¹,

Glickman²,

Shuman³

2008

Genes Dev.

107

179

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“…It is interesting to speculate whether this process might be enhanced by Ku-like proteins, which catalyze the recruitment of DNA ligase to DNA ends and ligation (68). Ku homologs have recently been identified in bacteria (68,235,236), and the Gam subfamily of Ku-like proteins is present in bacteria (Campylobacter spp., Neisseria spp., Haemophilus spp., E. coli O157:H7, and S. enterica serovar Typhi) and bacteriophage Mu (56).…”

Section: Mechanism Of Phage Module Exchange: Illegitimate Versus Homomentioning

confidence: 99%

Phages and the Evolution of Bacterial Pathogens: from Genomic Rearrangements to Lysogenic Conversion

Brüssow

Canchaya

Hardt

2004

Microbiol Mol Biol Rev

1,460

1,295

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Comparative genomics demonstrated that the chromosomes from bacteria and their viruses (bacteriophages) are coevolving. This process is most evident for bacterial pathogens where the majority contain prophages or phage remnants integrated into the bacterial DNA. Many prophages from bacterial pathogens encode virulence factors. Two situations can be distinguished: Vibrio cholerae, Shiga toxin-producing Escherichia coli, Corynebacterium diphtheriae, and Clostridium botulinum depend on a specific prophage-encoded toxin for causing a specific disease, whereas Staphylococcus aureus, Streptococcus pyogenes, and Salmonella enterica serovar Typhimurium harbor a multitude of prophages and each phage-encoded virulence or fitness factor makes an incremental contribution to the fitness of the lysogen. These prophages behave like “swarms” of related prophages. Prophage diversification seems to be fueled by the frequent transfer of phage material by recombination with superinfecting phages, resident prophages, or occasional acquisition of other mobile DNA elements or bacterial chromosomal genes. Prophages also contribute to the diversification of the bacterial genome architecture. In many cases, they actually represent a large fraction of the strain-specific DNA sequences. In addition, they can serve as anchoring points for genome inversions. The current review presents the available genomics and biological data on prophages from bacterial pathogens in an evolutionary framework

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“…Moreover, DNA-PK cs appears to regulate telomere length (28,36,69) and prevent GCRs (2,31,32). Ku is a heterodimeric protein of 70-and 86-kDa subunits that is conserved from prokaryotes (21,82) to humans. Ku binds in a sequence-nonspecific fashion to all double-stranded DNA ends, including 5Ј and 3Ј overhangs, blunt ends, duplex DNA ending in stem-loop structures, and telomeres (reviewed in references 39 and 75).…”

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confidence: 99%

Regulation of Telomere Length and Suppression of Genomic Instability in Human Somatic Cells by Ku86

Myung

Ghosh

Fattah

et al. 2004

Molecular and Cellular Biology

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Ku86 plays a key role in nonhomologous end joining in organisms as evolutionarily disparate as bacteria and humans. In eukaryotic cells, Ku86 has also been implicated in the regulation of telomere length although the effect of Ku86 mutations varies considerably between species. Indeed, telomeres either shorten significantly, shorten slightly, remain unchanged, or lengthen significantly in budding yeast, fission yeast, chicken cells, or plants, respectively, that are null for Ku86 expression. Thus, it has been unclear which model system is most relevant for humans. We demonstrate here that the functional inactivation of even a single allele of Ku86 in human somatic cells results in profound telomere loss, which is accompanied by an increase in chromosomal fusions, translocations, and genomic instability. Together, these experiments demonstrate that Ku86, separate from its role in nonhomologous end joining, performs the additional function in human somatic cells of suppressing genomic instability through the regulation of telomere length.Most human tumors display some sort of chromosomal instability, ranging from minor DNA sequence changes to GCRs (gross chromosomal rearrangements) and aneuploidy (reviewed in references 53 and 68). These genomic alterations are often the causative event(s) in the transformation of a normal cell into a neoplastic cell. This occurs when the alteration results in the activation of proto-oncogenes or the inactivation of tumor suppressor genes and/or by the acquisition of a mutator phenotype (reviewed in reference 51). There are at least three proposed pathways by which chromosomal rearrangements may originate: (i) checkpoint defects (reviewed in reference 46), (ii) stalled replication fork collapse (reviewed in reference 15), and (iii) telomere dysfunction (reviewed in reference 54). Studies with yeast have demonstrated that a deficiency in any of these three pathways enhances chromosome loss and GCRs by up to 2 to 3 orders of magnitude (reviewed in reference 46). Similarly, in higher eukaryotes, mutations in genes regulating checkpoints and the repair of stalled replication forks result in a highly elevated frequency of GCRs (reviewed in references 38 and 78). Finally, in mice and humans, evidence is accumulating that the dysfunction of telomeres may be the driving force in the generation of genomic instability, which is strongly linked to cancer predisposition (reviewed in reference 54).Telomeres are the terminal structures of linear chromosomes. Telomeres appear to perform at least two functions: (i)

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The Gam protein of bacteriophage Mu is an orthologue of eukaryotic Ku

Abstract: Mu bacteriophage inserts its

Cited by 57 publications

References 25 publications

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

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

Phages and the Evolution of Bacterial Pathogens: from Genomic Rearrangements to Lysogenic Conversion

Regulation of Telomere Length and Suppression of Genomic Instability in Human Somatic Cells by Ku86

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