NHEJ regulation by mating type is exercised through a novel protein, Lif2p, essential to the Ligase IV pathway

Frank-Vaillant, Marie; Marcand, Stéphane

doi:10.1101/gad.206801

Cited by 156 publications

(135 citation statements)

References 39 publications

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“…Both XLF and Nej1 were identified by two-hybrid detection of heterotypic interactions with XRCC4/Lif1 [21,25], interactions which we verify and refine here by both two-hybrid and pull-down methods (Figure 2). Prediction of a similar fold of XLF/Nej1 and XRCC4/Lif1 subsequently suggested the possibility of coiled-coil-dependent heterodimerization [25,28,31] (Figure 1).…”

Section: Heterotypic Interactionssupporting

confidence: 70%

“…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%

“…Nej1 explains the mating type-dependent regulation of yeast NHEJ by virtue of its selective expression in haploid cells [21,22]. This fact, combined with the inability of standard computational approaches to reveal apparent Nej1 homologues outside of budding yeasts, led to the supposition that Nej1 was not a universal NHEJ protein.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Heterotypic Interactionssupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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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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“…Cell-type specific regulation of the DNA damage repair method has also been demonstrated. For example haploid yeast exert mating type control of NHEJ (Frank-Vaillant and Marcand, 2001). In addition alternative pathways for DSB repair can effectively compete with one another at the same break site (Fishman-Lobell et al, 1992;Tutt et al, 2001).…”

Section: Unresolved Issuesmentioning

confidence: 99%

Does age influence loss of heterozygosity?

Carr

Gottschling

2008

Experimental Gerontology

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The striking correlation between advanced age and an increased incidence of cancer has led investigators to examine the influence of aging on genome maintenance.Because loss of heterozygosity (LOH) can lead to the inactivation of tumor suppressor genes, and thus carcinogenesis, understanding the affect of aging on this type of mutation event is particularly important. Several factors may affect the rate of LOH, including an increase in the amount of DNA damage, specifically double-strand breaks (DSB), and the ability to efficiently repair this damage via pathways that minimize the loss of genetic information. Because of experimental constraints, there is only suggestive evidence for a change in the rate of DNA damage as humans age. However, recent studies in model organisms find that there are increased rates of LOH with age, and that repair of DNA damage occurs via a different pathway in old cells versus young cells. We speculate that the age-dependent change in DNA repair may explain why there is increased LOH, and that the findings from these model organisms may extend to humans.

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“…Diploid MATa/MATa yeasts demonstrate lower NHEJ activity than their haploid MATa and MATa counterparts. This regulation of NHEJ in diploids is correlated with the specific downregulated expression of Nej1p/Lif2p in these cells as compared to haploids (Frank-Vaillant and Marcand, 2001;Kegel et al, 2001;Ooi et al, 2001;Valencia et al, 2001). The ectopic expression of Nej1p/ Lif2p restores NHEJ to some extent.…”

Section: Nhej and Csrmentioning

confidence: 86%

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

et al. 2007

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The immune system is the site of intense DNA damage/ modification, which occur during the development and maturation of B and T lymphocytes. V(D)J recombination is initiated by the Rag1 and Rag2 proteins and the formation of a DNA double-strand break (DNA dsb). This DNA lesion is repaired through the use of the nonhomologous end-joining (NHEJ) pathway, several factors of which have been identified through the survey of immunodeficient conditions in humans and mice. Upon antigenic recognition in secondary lymphoid organs, mature B cells further diversify their repertoire through class switch recombination (CSR). CSR is a region-specific rearrangement process triggered by the activation-induced cytidine deaminase factor and also proceeds through the introduction of DNA dsb. However, unlike V(D)J recombination, CSR does not rely strictly on NHEJ for the repair of the DNA lesion. Instead, CSR, but not V(D)J recombination, requires the major factors of the DNA damage response. V(D)J recombination and CSR thus represent an interesting paradigm to study the regulation among the various DNA repair pathways. Oncogene (2007) 26, 7780-7791; doi:10.1038/sj.onc.1210875 Keywords: V(D)J recombination; class switch recombination; SCID; Artemis; Cernunnos; NHEJ V(D)J recombination and CSR: two rearrangement processes that shape the immune system repertoire B and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the B-cell receptor and T-cell receptor, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Figure 1) which assembles previously scattered Variable (V), Diversity (D) and Joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism (Tonegawa, 1983). The reaction is initiated by the lymphoid-specific factors, Rag1 and Rag2, which recognize recombination signal sequences (RSS) that flank all V, D and J gene units and introduce a DNA dsb at the border of the RSS (see Dudley et al. (2005) for a review on V(D)J recombination). The resulting DNA double-strand break (DNA dsb) is resolved by the ubiquitous DNA repair machinery known as non-homologous end-joining (NHEJ). The convergent efforts of scientists in the immunology and DNA repair fields were decisive in defining the various actors and molecular mechanisms of this DNA repair pathway over the years as will be discussed below.The terminal maturation of B lymphocytes, which occurs in germinal centres of secondary lymphoid organs upon antigen recognition, is accompanied by two additional molecular processing of immunoglobulin genes that increase the efficiency of the humoral response: (1) the class switch recombination (CSR, Figure 2) exchanges the immunoglobulin (Ig) constant region (CH), thus modifying the function of the Ig without altering its antigenic specificity (Manis et al., 2002b) and (2) somatic hypermutations are introduced in the Ig variable domains, thus increasing their affinity for antigen (Papavasiliou and Schatz, 2002). These two events ar...

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NHEJ regulation by mating type is exercised through a novel protein, Lif2p, essential to the Ligase IV pathway

Cited by 156 publications

References 39 publications

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

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

Does age influence loss of heterozygosity?

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

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