NEJ1 controls non-homologous end joining in Saccharomyces cerevisiae

Valencia, Maria A.; Bentele, Marc; Vaze, Moreshwar B.; Herrmann, G.; Kraus, Eliayhu; Lee, Sang Eun; Schär, Primo; Haber, James E.

doi:10.1038/414666a

Cited by 213 publications

(195 citation statements)

References 28 publications

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“…The kinetic delay resulting from unproductive homology search may have triggered the DNA damage response that favors as a consequence SSA after having attempted HR. Interestingly, Nej1 is the target of transcriptional down-regulation to inhibit NHEJ in diploid MATa/a budding yeast cells (Frank-Vaillant and Marcand 2001;Kegel et al 2001;Valencia et al 2001). As Nej1 acts late in the reaction at the ligation step in conjunction with DNA ligase 4 and its cofactor Lif1 (XRCC4 in humans) (Callebaut et al 2006;Chen and Tomkinson 2011), it may suggest that earlier end-joining steps do not preclude subsequent HR.…”

Section: Dsb-repair Pathway Choice or How Resection Commits To Hrmentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

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Section: Dsb-repair Pathway Choice or How Resection Commits To Hrmentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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“…The involvement of a third protein in the DNA ligase IV complex was first suggested by discovery of the yeast NHEJ protein Nej1 and the observation that it interacts with Lif1 [20][21][22][23][24]. Nej1 explains the mating type-dependent regulation of yeast NHEJ by virtue of its selective expression in haploid cells [21,22].…”

Section: Introductionmentioning

confidence: 99%

Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4

Deshpande

Wilson

2007

DNA Repair

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The nonhomologous end joining (NHEJ) pathway of double-strand break repair depends on DNA ligase IV and its interacting partner protein XRCC4 (Lif1 in yeast). A third yeast protein, Nej1, interacts with Lif1 and supports NHEJ, similar to the distantly related mammalian Nej1 orthologue XLF (also known as Cernunnos). XRCC4/Lif1 and XLF/Nej1 are themselves related and likely fold into similar coiled-coil structures, which suggests many possible modes of interaction between these proteins. Using yeast two-hybrid and co-precipitation methods we examined these interactions and the protein domains required to support them. Results suggest that stable coiled-coil homodimers are a predominant form of XLF/Nej1, just as for XRCC4/Lif1, but that similar heterodimers are not. XLF-XRCC4 and Nej1-Lif1 interactions were instead mediated independently of the coiled coil, and by different regions of XLF and Nej1. Specifically, the globular head of XRCC4/Lif1 interacted with N-and C-terminal domains of XLF and Nej1, respectively. Direct interactions between XLF/Nej1 and DNA ligase IV were also observed, but again appeared qualitatively different than the stable coiled coil-mediated interaction between XRCC4/Lif1 and DNA ligase IV. The implications of these findings for DNA ligase IV function are considered in light of the evolutionary pattern in the XLF/ XRCC4 and XLF/Nej1 family.

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“…Despite this localization, it is now clear that the defect of cells lacking these factors in NHEJ is mainly indirect because deletion of the SIR genes leads to pseudodiploidy in yeast as a result of loss of silencing at the silent mating type loci (22,23). This results in expression of the a͞␣ transcriptional regulator that suppresses a number of haploid-specific genes, including NEJ1, which encodes for a protein required for NHEJ (24,25). Therefore, the main defect in NHEJ in sir mutants is due to the loss of silencing at the silent mating type loci.…”

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confidence: 99%

Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair

Jazayeri

McAinsh

Jackson

2004

Proc. Natl. Acad. Sci. U.S.A.

148

114

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There are two main pathways in eukaryotic cells for the repair of DNA double-strand breaks: homologous recombination and nonhomologous end joining. Because eukaryotic genomes are packaged in chromatin, these pathways are likely to require the modulation of chromatin structure. One way to achieve this is by the acetylation of lysine residues on the N-terminal tails of histones. Here we demonstrate that Sin3p and Rpd3p, components of one of the predominant histone deacetylase complexes of Saccharomyces cerevisiae, are required for efficient nonhomologous end joining. We also show that lysine 16 of histone H4 becomes deacetylated in the proximity of a chromosomal DNA doublestrand break in a Sin3p-dependent manner. Taken together, these results define a role for the Sin3p͞Rpd3p complex in the modulation of DNA repair.I n eukaryotic cells, the genome is compacted into chromatin.The basic unit of chromatin is the nucleosome, which is composed of the conserved core histones H2A, H2B, H3, and H4. The structure of nucleosomal DNA is further compacted by a range of other factors, including proteins such as the linker histone H1 that binds to DNA between the nucleosome repeats (1). Various DNA-templated processes such as transcription, replication, and DNA repair take place in the context of chromatin and so must involve the manipulation of nucleosomes. One way to achieve this is through the reversible acetylation, phosphorylation, ubiquitination, or ADP-ribosylation of the histone tails that extend to the accessible surface of the nucleosome core particle (2). It has been proposed that combinations of these modifications create a ''histone code'' that is recognized by other proteins to bring about specific downstream events (3).The most extensive body of data has been accumulated for the effect of nucleosome modifications in transcription (4). However, there is growing evidence that there is cross-talk between chromatin and DNA damage response and repair pathways. This is particularly well established for nucleotide excision repair (NER), in which several chromatin remodeling and modification factors have been implicated (ref. 5 and references therein). As discussed further below, there is also evidence for the importance of chromatin modification in the repair of DNA doublestrand breaks (DSBs), which are generated by ionizing radiation and a range of chemotherapeutic agents. Given the highly recombinogenic and cytotoxic nature of such lesions (6, 7), the impact of chromatin on DSB repair is likely to be of considerable biological importance.There are two principle mechanisms for the repair of DNA DSBs: homologous recombination (HR) and nonhomologous end joining (NHEJ). The former requires genes in the RAD52 epistasis group and relies on extensive homology between the damaged DNA and an undamaged partner [sister chromatid or homologous chromosome (8)]. By contrast, NHEJ requires little or no homology between the recombining molecules (9). Key components of the NHEJ machinery in mammals include the Ku70͞Ku80 heterodimer an...

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NEJ1 controls non-homologous end joining in Saccharomyces cerevisiae

Cited by 213 publications

References 28 publications

Regulation of Recombination and Genomic Maintenance

Regulation of Recombination and Genomic Maintenance

Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4

Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair

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