HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 20, 13857-13860, May 19, 2006

This Article Abstract Full Text (PDF) Supplemental Data All Versions of this Article: 281/20/13857    most recent C500473200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Callebaut, I. Articles by de Villartay, J.-P. Search for Related Content PubMed PubMed Citation Articles by Callebaut, I. Articles by de Villartay, J.-P. Social Bookmarking                      What's this?

Cernunnos Interacts with the XRCC4·DNA-ligase IV Complex and Is Homologous to the Yeast Nonhomologous End-joining Factor Nej1^*

Isabelle Callebaut¹², Laurent Malivert¹³, Alain Fischer^¶||, Jean-Paul Mornon, Patrick Revy^¶4, and Jean-Pierre de Villartay^¶||5

From the Département de Biologie Structurale, Institut de Minéralogie et de Physique des Milieux Condensés, CNRS UMR7590, Universités Paris 6 et Paris 7, Paris, F-75005 France, the INSERM, Hôpital Necker-Enfants Malades, U768, UnitéDéveloppement Normal et Pathologique du Système Immunitaire, Paris, F-75015 France, the ^¶Université Paris Descartes, Faculté de Médecine René Descartes, Paris, F-75005 France, and the ^||Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Unité d'Immunologie et d'Hématologie, Paris F-75015, France

Received for publication, December 20, 2005 , and in revised form, March 28, 2006.

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
DNA double strand breaks are considered as the most harmful DNA lesions and are repaired by either homologous recombination or nonhomologous end joining (NHEJ). A new NHEJ factor, Cernunnos, has been identified, the defect of which leads to a severe immunodeficiency condition associated with microcephaly and other developmental defects in humans. This presentation is reminiscent to that of DNA-ligase IV deficiency and suggests a possible interplay between Cernunnos and the XRCC4·DNA-ligase IV complex. We show here that Cernunnos physically interacts with the XRCC4·DNA-ligase IV complex. Moreover, a combination of sensitive methods of sequence analysis revealed that Cernunnos can be associated with the XRCC4 family of proteins and that it corresponds to the genuine homolog of the yeast Nej1 protein. Altogether these results shed new lights on the last step, the DNA religation, of the NHEJ pathway.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
DNA double strand breaks are caused by exposure to ionizing radiation or chemical agents. They also result from physiological DNA rearrangements occurring during meiosis or, in vertebrate cells, during specialized recombination events underlying the development and maturation of the adaptive immune system (1). Two main mechanisms were developed in eukaryotic cells for efficient DNA double strand break repair: the accurate homologous recombination and the nonhomologous end-joining (NHEJ)⁶ pathways (see Ref. 2 for review). Six mammalian factors constitute the core NHEJ apparatus: the Ku70/ Ku80 heterodimer, the DNA-PKcs kinase, the Artemis endonuclease, and the XRCC4·DNA-ligase IV complex responsible for the final ligation step (3). Additional NHEJ factors have been recognized in yeast, such as Nej1, which interacts with the yeast XRCC4 homolog Lif1p (4–6). We recently identified a novel human NHEJ DNA repair factor, Cernunnos, the defect of which results in immune deficiency and microcephaly (7). One striking characteristic of Cernunnos patients is their clinical and biological resemblance with DNA-ligase IV patients (8–10). This includes microcephaly and immune deficiency, mostly characterized by a severely impaired development of B and T lymphocytes. Both conditions are caused by a faulty NHEJ, which translates into increased cellular sensitivity to DNA-damaging agents and the impaired capacity to join double-stranded DNA ends in vitro and in vivo. This parallel prompted us to hypothesize that Cernunnos may be acting at the same level as the XRCC4·DNA-ligase IV complex during DNA repair and may indeed incorporates into this complex.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Antibodies and Immunoprecipitation—The Cernunnos Orf, together with a C terminus V5 or myc epitope tag, was cloned into the pCDNA3.1 vector (7) and used to transfect 293T cells. Cells were lysed for 20 min on ice in 1 ml of lysis buffer (1x TNE) containing 50 mM Tris (pH 8.0), 2 mM EDTA, 0.5% Nonidet P-40, 1% phosphatase inhibitor cocktails (1 and 2, Sigma), and protease inhibitor (Roche Applied Science). One mg of cell lysate was first precleared with rabbit or mouse IgG (Santa Cruz Biotechnology) and then incubated (1 h, 4 °C) with 20 µl of prewashed protein A-Sepharose beads (Amersham Biosciences). Immunoprecipitations were performed on precleared lysates using anti-V5 (Invitrogen), anti-DNA-ligase IV (Acris), and anti-XRCC4 (Serotec) rabbit polyclonal or murine monoclonal anti-myc (Santa Cruz Biotechnology) antibodies for 1 h at 4 °C. Immune complexes were collected with protein A-Sepharose beads. Immunoprecipitates were analyzed by Western blotting with murine monoclonal anti-V5 (Invitrogen), anti-myc, or rabbit polyclonal anti-DNA-ligase IV and anti-XRCC4 antibodies.

In Silico Sequence Analysis: Molecular Modeling—PSI-BLAST (11) searches were performed at NCBI (www.ncbi.nlm.nih.gov/blast) using the nr data base (2,920,020 sequences) (BLAST2.2.12, inclusion threshold E-value = 0.005). Guidelines to the use of hydrophobic cluster analysis (HCA) are given in Refs. 12 and 13. Modeling of three-dimensional structure was done using Modeler (14).

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Cernunnos Interacts with the XRCC4·DNA-Ligase IV Complex—We searched for a possible interaction of Cernunnos with the XRCC4·DNA-Ligase IV complex by transfecting 293T cells with a V5 epitope-tagged form of Cernunnos followed by immunoprecipitation experiments. As shown in Fig. 1A, the immunoprecipitation of Cernunnos via the V5 tag co-precipitated DNA-ligase IV (lane 6, upper panel). Conversely, the immunoprecipitation of either endogenous DNA-ligase IV (lane 8) or XRCC4 (lane 10) co-precipitated the transfected Cernunnos protein (revealed by anti-V5 antibody, bottom panel) in both cases. The same co-immunoprecipitation results were obtained (Fig. 1B) using the myc epitope-tagged version of Cernunnos. This demonstrates that XRCC4, DNA-ligase IV, and Cernunnos are part of a same complex. While this manuscript was under review, Ahnesorg et al. (15) reported on the identification of XLF, a factor identical to Cernunnos, through its physical interaction with XRCC4.

Cernunnos Is Homologous to XRCC4—To get further insight into the role of Cernunnos in NHEJ, we performed careful bioinformatics analysis of its protein sequence. Using HCA, a sensitive two-dimensional approach that is well suited to analyze the two-dimensional texture of proteins and compare their secondary structures (12, 13), we first identified in the Cernunnos sequence a globular domain, ranging from amino acids 1–230. Using this sequence as query in PSI-BLAST (11) searches with default parameters, we detected different homologs of Cernunnos at convergence by iteration 4. A few of these sequences are shown in Fig. 2A (yellow box). A marginal similarity with a putative DNA double strand break repair protein from Arabidopsis thaliana was observed just above the threshold E-value (E-value = 0.28; 16% of identity over 108 amino acids). This protein turned out to be the plant XRCC4 homolog (white box in Fig. 2A), sharing with the human protein 24% sequence identity over the head and stalk regions. The similarity reported by PSI-BLAST between human Cernunnos and Arabidopsis XRCC4 encompasses the globular "head" domain of XRCC4 and the initial portion of the helical stalk, the overall region that promotes XRCC4 dimerization (16–20). The similarity was supported at the two-dimensional level using HCA, revealing the conservation of the secondary structures forming the head domain, which contains a -sandwich and two -helices, as well as the helical stalk (Figs. 2A and 3A and data not shown). Most of the conserved features correspond to hydrophobicity (positions in which hydrophobicity is conserved are green in Fig. 2, with highly conserved aromatic residues in purple). These amino acids mainly participate in the head core structure or are involved in the contact with the initial portion of the stalk (e.g. Trp¹³ (W13) in Fig. 3A). Only a few surface-exposed residues are conserved, such as Phe¹¹⁷ and Trp¹¹⁹, which may be part of a potential interaction site (Fig. 3A). The finding of deleterious missense mutations (R57G and C123R in Fig. 3A) in the vicinity of these residues in patients (7) further strengthens the likely functional significance of this region of Cernunnos. Other PSI-BLAST searches were performed using Cernunnos homologous sequences as queries, which highlighted marginal similarities with additional XRCC4 proteins (E-value = >0.001), also supported at the two-dimensional level (data not shown). This first finding thus reveals a novel family of structurally similar proteins, gathering XRCC4 and Cernunnos. When our manuscript was under review, a similar conclusion was drawn by Ahnesorg et al. (15), who used fold recognition methods to unravel the structural relationship between Cernunnos/XLF and XRCC4. However, these automatic methods proposed two different alignments of Cernunnos/XLF with the two available experimental structures of XRCC4, which yet share an almost identical sequence (99% identity; see Fig. 1 of supplemental data in Ref. 15). Here, we propose a refined alignment of the two protein sequences, performed using the sensitive HCA methodology. This one benefited from the additional evolutionary information coming from the direct consideration of the whole Cernunnos and XRCC4 families. Accordingly, the alignment of the Cernunnos family sequences well conserved the structural invariants constituting the XRCC4 hydrophobic core (positions are shaded green and violet in Fig. 2A). These features were reinforced when considering the Nej1 sequences (see below).

View larger version (53K): [in this window] [in a new window]   FIGURE 1. Cernunnos interacts with the XRCC4·DNA-ligase IV complex. A, whole cell lysates (WCL) were obtained from 293T cells transfected (+) or not (–) with a V5 epitope tag Cernunnos expression construct. One mg of protein was immunoprecipitated (IP) with irrelevant antibodies (IgG, lanes 3 and 4), anti-V5 (lanes 5 and 6), anti-DNA-ligase IV (lanes 7 and 8), or anti-XRCC4 (lanes 9 and 10) antibodies, blotted, and revealed by anti-DNA-ligase IV (top panel) or anti-V5 (bottom panel) antibodies. B, whole cell lysates obtained from Cernunnos-myc-transfected 293T cells were precipitated using anti-myc as above and the immunoprecipitates revealed using anti-DNA ligase IV, anti-XRCC4, and anti-myc antibodies. C, whole cell lysates obtained from Cernunnos-V5- and Cernunnos-myc-co-transfected 293T cells were immunoprecipitated with anti-V5 or anti-myc and the immunoprecipitates revealed by anti-V5 and anti-myc antibodies. WB, Western blot.

The finding that Cernunnos is related to XRCC4 on the one hand and the demonstration that Cernunnos interacts with the XRCC4·DNA-ligase IV complex on the other hand raises the interesting issue of the possible combinatorial associations of these two proteins within XRCC4/Cernunnos dimers and/or tetramers (Fig. 3B) and the possible functional consequences of these various combinations. As a first way to address this issue, we performed co-immunoprecipitation experiments following cotransfection of 293T cells with V5 epitope-tagged Cernunnos and myc epitope-tagged Cernunnos. As shown in Fig. 1C, immunoprecipitation with anti-V5 and anti-myc co-precipitated the Cernunnos-myc and Cernunnos-V5, respectively. This suggests that Cernunnos, as described for XRCC4, can form homoduplexes or at least that two Cernunnos molecules are part of the same complex as also demonstrated by Ahnesorg et al. (15). Although the definite answers to these questions need further in vitro and in vivo investigations, one can already postulate that, given the embryonic lethality of XRCC4 mutant mice (21) and the severe immunodeficiency and developmental anomalies of human Cernunnos-deficient patients (7), these two factors, although part of the same complex, are not redundant. Moreover, overexpression of XRCC4 in Cernunnos-deficient cells does not reverse the defective V(D)J recombination (supplemental Fig. S1) indicating that these two factors play specific parts during the NHEJ process.

Cernunnos Is Homologous to Yeast Nej1—Several putative partners of XRCC4 and DNA-ligase IV have been identified in mammals and yeast. One of these, Nej1/Lif2p, has been identified in Saccharomyces cerevisiae through its interaction with Lif1p, the yeast homolog of XRCC4, and by virtue of the fact that it is transcriptionally repressed/expressed in yeast diploid and haploid cells respectively (4–6, 22). Nej1 thus appears as a critical regulator of NHEJ activity in yeast cells undergoing mating type switching. Moreover, ectopic expression of Nej1 restores NHEJ in MATa/MAT diploid cells to some extent (4–6). To date no homolog of Nej1 has been identified in other organisms, including the fission yeast Schizosaccharomyces pombe. Given their interaction with the XRCC4·DNA-ligase IV complex and their similar molecular weight, we tackled the idea that Cernunnos may represent the genuine mammalian Nej1 homolog.

Cernunnos was identified from human to several yeast species (S. pombe, Neurospora crassa, Gibberella zeae, Magnaporthe grisea, Aspergillus nidulans, Debaryomyces hansenii, Yarrowia lipolytica) by data base mining (Fig. 2A, yellow and green boxes, and data not shown) but intriguingly could not be found within the PSI-BLAST significant results in the S. cerevisiae species. No candidate could be found within the non-significant alignments either. Taking the opposite approach, using the S. cerevisiae Nej1 sequence as query in a PSI-BLAST search (same parameters as above) highlighted marginal similarities with two yeast sequences (Kluyveromyces lactis (E-value = 0.038) and Aphis gossypii (E-value = 0.14), Fig. 2A, blue box), which could be further supported at the two-dimensional level (data not shown). To further broaden the analysis, these loose similarities were quoted with significant E-values and extended to other yeast species in a reciprocal strategy. For example starting from the A. gossypii sequence, we highlighted significant similarities at convergence by iteration 4 with the S. cerevisiae Nej1 (E-value = 2 x 10^–29) but also with two other yeast species (Candida albicans (E-value = 8 x 10^–62) and D. hansenii (E-value = 9 x 10^–76) ("Nej1" sequences in Fig. 2, blue and green boxes). Surprisingly, the D. hansenii Nej1 sequence highlighted here (GenBank^TM identifier 49657009) was identical to the D. hansenii Cernunnos sequence identified above, making this yeast species the critical intermediate sequence that reveals the Nej1/Cernunnos relationship (green box in Fig. 2). Indeed, no significant, or marginal, similarities could be directly detected between Nej1 and the human Cernunnos sequence.

View larger version (74K): [in this window] [in a new window]   FIGURE 2. Multiple sequence alignments of members of the Cernunnos/Nej1 family and XRCC4 proteins. A, the "head." The alignment was constructed on the basis of PSI-BLAST results and manually refined using HCA. The D. hansenii protein has been significantly detected as a Cernunnos homolog as well as a Nej1 homolog (horizontal green box at the intersection of the yellow (Cernunnos) and blue (Nej1) boxes). It thus constitutes the intermediate protein, which allows revealing the relationship between Nej1 and Cernunnos. There is 15.8% sequence identity between the sequences of human Cernunnos and D. hansenii Cernunnos/Nej1 (119 aligned positions) and 10.3% between the sequences of D. hansenii Cernunnos/Nej1 and S. cerevisiae Nej1 (116 aligned positions). Secondary structures, as observed in the three-dimensional structures of XRCC4 (Protein Data Bank identifier 1FU1) are indicated above the XRCC4 sequences. Coloring scheme: white letters on a green background, positions in which hydrophobicity is conserved (on a purple background, conserved aromatic residues (FWY)); black letters on a gray background, other noticeable conserved positions. A, C, and T, which can substitute for hydrophobic residues (VILFMYW), are reported accordingly. GenBankTM identifiers (gi) are: 12084562 (Homo sapiens XRCC4), 9800643 (A. thaliana XRCC4), 50415440 (Xenopus laevis Cernunnos), 47550775 (Danio rerio Cernunnos), 40741672 (A. nidulans Cernunnos), 7160259 (S. pombe Cernunnos), 49657009 (D. hansenii Cernunnos/Nej1), 46442216 (C. albicans Nej1), 49645129 (K. lactis Nej1), and 44986293 (A. gossypii Nej1). Cernunnos sequence is from EMBL AJ972687 [GenBank] . B, the DNA-ligase IV interaction region. The alignment gathers sequences of XRCC4 and Cernunnos from several species. XRCC4, but not Cernunnos, is found in plants (A. thaliana). The conserved sequences found in a similar location within the stalk in yeast Cernunnos/Nej1 proteins is not shown, as the corresponding profile poorly matches those of metazoan sequences. GenBankTM identifiers (gi) are as the same as in B and also 50761983 (Gallus gallus XRCC4), 49257218 (X. laevis XRCC4), 41387194 (D. rerio XRCC4), and 50750592 (G. gallus Cernunnos).

Conclusion—We demonstrate here that the newly identified DNA repair factor, Cernunnos, interacts with the XRCC4·DNA-ligase IV complex, is the mammalian homolog of the yeast Nej1 factor, and that both belong to an extended XRCC4 family. These findings have several important implications. As we discussed above, the similarity between XRCC4 and Cernunnos raises the question of the true nature of the XRCC4·Cernunnos·DNA-ligase IV complex. Do both proteins always participate in the same complex? What are the rules governing their combinatorial association? What is the exact specific role that both factors play during the catalysis of DNA end joining? Analyzing mutations identified in patients is often of great help to describe an important region of a protein but sometimes can be misleading in case of hypomorphic mutations. Indeed, although the 2BN cells appear to harbor the more drastic mutation (a frameshift at the fifth amino acid) (15), the clinical presentation appears somehow less severe than the other described Cernunnos mutants (7, 23). In particular, the 2BN patient did not present with microcephaly. This strongly suggests that 2BN harbors a hypomorphic Cernunnos mutation through the translation reinitiation on a downstream methionine as proposed (15). A very similar situation has been described in the case of a particular mutation in the Rag1 gene, which in theory should lead to a T-B-SCID condition but, instead, appears as leaky, leading to the development of lymphocytes to some extent (24, 25).

View larger version (27K): [in this window] [in a new window]   FIGURE 3. Model for the Cernunnos three-dimensional structure. A, model of the dimeric three-dimensional structure of the human Cernunnos head domain and the initial portion of the stalk (up to residue Gly141). The model was built on the basis of the alignment shown in Fig. 2, using the nearly symmetric dimer of XRCC4 as a template (Protein Data Bank identifier 1FU1 (16)). Secondary structures are colored as described in the legend to Fig. 2. The white/brown helices (modeled on the XRCC4 stalk, sequence alignment not shown) recall the overall architecture of the XRCC4 protein dimer (stalk). B, putative combinatorial association within the XRCC4·DNA-ligase IV·Cernunnos complex. XRCC4 protein (orange) has been described as dimer in association with DNA-ligase IV (blue) or tetramers (16–20). Several combinatorial associations with Cernunnos (green) can be hypothesized.

Nej1 has been considered in yeast as a cell type NHEJ regulator based on its specific transcriptional down-regulation in MATa/MAT diploid cells (4–6, 22). Indeed NHEJ is influenced in yeast by the mating type status of the cells. Diploid MATa/MAT cells demonstrate lower NHEJ activity compared with haploid cells expressing either MATa or MAT (27–29). Ectopic expression of Nej1 in MATa/MAT diploid cells restores NHEJ in these cells to some extent (4–6). The exact role of Nej1 during NHEJ in yeast is unknown. One controversial study had suggested that Nej1 could facilitate the nuclear localization of Lif1 (4). However, we did not find any abnormal XRCC4 subcellular distribution in Cernunnos-deficient cells from a Cernunnos-deficient patient referenced as P2 in Buck et al. (7) (supplemental Fig. S2). Likewise, a normal nuclear localization of XRCC4 was noted in 2BN cells (15). This observation is in agreement with results described in another Nej1/Lif1 study in yeast (6). Whether the Cernunnos level could somehow regulate NHEJ in mammalian cells is another interesting issue. It would be of particular interest to assess the expression of Cernunnos during the various phases of the cell cycle or in cells known to preferentially use homologous recombination such as during meiosis.

Altogether, the link we made between Cernunnos and Nej1 should help design new experiments to clarify the functional role of both factors during NHEJ-mediated DNA repair.

	FOOTNOTES

 
^* This work was supported by institutional grants from INSERM as well as grants from the Ligue National contre le Cancer (Equipe Labellisée LA LIGUE 2005, EL2005.LNCC/JPDV1), the Commissariat à l'Energie Atomique (LRC-CEA No. 40V), and the INCa/Cancéropôle IdF. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data and Figs. S1 and S2.

¹ These authors contributed equally to the work.

³ Supported by Ministere de l'Education Nationale, de l'Enseignement Supérieur, et de la Recherche.

⁴ Scientist from the CNRS.

² To whom correspondence may be addressed: Dépt. de Biologie Structurale, IMPMC, CNRS UMR 7590, Universités Paris 6 et Paris 7, case 115, 4 place Jussieu, 75252 Paris Cedex 05, France. Tel.: 33-1-44-27-45-87; Fax: 33-1-44-27-37-85; E-mail: IsabelleCallebaut{at}impmc.jussieu.fr. ⁵ To whom correspondence may be addressed: INSERM U768, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France. Tel.: 33-1-44-49-50-81; Fax: 33-1-42-73-06-40; E-mail: devillar{at}necker.fr.

⁶ The abbreviations used are: NHEJ, nonhomologous end joining; HCA, hydrophobic cluster analysis.

⁷ I. Callebaut and J.-P. Mornon, unpublished observations.

	ACKNOWLEDGMENTS

 
We thank Dr. Stéphane Marcand for helpful discussions on Nej1.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 

1. Revy, P., Buck, D., Le Deist, F., and de Villartay, J. P. (2005) Adv. Immunol 87, 237–295[CrossRef][Medline] [Order article via Infotrieve]
2. Sancar, A., Lindsey-Boltz, L. A., Unsal-Kacmaz, K., and Linn, S. (2004) Annu. Rev. Biochem. 73, 39–85[CrossRef][Medline] [Order article via Infotrieve]
3. Weterings, E., and van Gent, D. C. (2004) DNA Repair (Amst.) 3, 1425–1435[CrossRef][Medline] [Order article via Infotrieve]
4. Valencia, M., Bentele, M., Vaze, M. B., Herrmann, G., Kraus, E., Lee, S. E., Schar, P., and Haber, J. E. (2001) Nature 414, 666–669[CrossRef][Medline] [Order article via Infotrieve]
5. Frank-Vaillant, M., and Marcand, S. (2001) Genes Dev. 15, 3005–3012[Abstract/Free Full Text]
6. Kegel, A., Sjostrand, J. O., and Astrom, S. U. (2001) Curr. Biol. 11, 1611–1617[CrossRef][Medline] [Order article via Infotrieve]
7. Buck, D., Malivert, L., de Chasseval, R., Barraud, A., Fondanèche, M. C., Sanal, O., Plebani, A., Stéphan, J. L., Hufnagel, M., Le Deist, F., Fischer, A., Durandy, A., de Villartay, J. P., and Revy, P. (2006) Cell 124, 287–299[CrossRef][Medline] [Order article via Infotrieve]
8. O'Driscoll, M., Cerosaletti, K. M., Girard, P. M., Dai, Y., Stumm, M., Kysela, B., Hirsch, B., Gennery, A., Palmer, S. E., Seidel, J., Gatti, R. A., Varon, R., Oettinger, M. A., Neitzel, H., Jeggo, P. A., and Concannon, P. (2001) Mol. Cell 8, 1175–1185[CrossRef][Medline] [Order article via Infotrieve]
9. Ben-Omran, T. I., Cerosaletti, K., Concannon, P., Weitzman, S., and Nezarati, M. M. (2005) Am. J. Med. Genet. A 137, 283–287[Medline] [Order article via Infotrieve]
10. Buck, D., Moshous, D., de Chasseval, R., Ma, Y., Le Deist, F., Cavazzana-Calvo, M., Fischer, A., Casanova, J. L., Lieber, M. R., and De Villartay, J. P. (2006) Eur. J. Immunol. 36, 224–235[CrossRef][Medline] [Order article via Infotrieve]
11. Altschul, S. F., Madden, T. L., Schaffer, A. A., Zhang, J., Zhang, Z., Miller, W., and Lipman, D. J. (1997) Nucleic Acids Res. 25, 3389–3402[Abstract/Free Full Text]
12. Gaboriaud, C., Bissery, V., Benchetrit, T., and Mornon, J. P. (1987) FEBS Lett. 224, 149–155[CrossRef][Medline] [Order article via Infotrieve]
13. Callebaut, I., Labesse, G., Durand, P., Poupon, A., Canard, L., Chomilier, J., Henrissat, B., and Mornon, J. P. (1997) Cell Mol. Life Sci. 53, 621–645[CrossRef][Medline] [Order article via Infotrieve]
14. Sali, A., and Blundell, T. L. (1993) J. Mol. Biol. 234, 779–815[CrossRef][Medline] [Order article via Infotrieve]
15. Ahnesorg, P., Smith, P., and Jackson, S. P. (2006) Cell 124, 301–313[CrossRef][Medline] [Order article via Infotrieve]
16. Junop, M. S., Modesti, M., Guarne, A., Ghirlando, R., Gellert, M., and Yang, W. (2000) EMBO J. 19, 5962–5970[CrossRef][Medline] [Order article via Infotrieve]
17. Lee, K. J., Huang, J., Takeda, Y., and Dynan, W. S. (2000) J. Biol. Chem. 275, 34787–34796[Abstract/Free Full Text]
18. Modesti, M., Junop, M. S., Ghirlando, R., van de Rakt, M., Gellert, M., Yang, W., and Kanaar, R. (2003) J. Mol. Biol. 334, 215–228[CrossRef][Medline] [Order article via Infotrieve]
19. Modesti, M., Hesse, J. E., and Gellert, M. (1999) EMBO J. 18, 2008–2018[CrossRef][Medline] [Order article via Infotrieve]
20. Sibanda, B. L., Critchlow, S. E., Begun, J., Pei, X. Y., Jackson, S. P., Blundell, T. L., and Pellegrini, L. (2001) Nat. Struct. Biol. 8, 1015–1019[CrossRef][Medline] [Order article via Infotrieve]
21. Gao, Y., Sun, Y., Frank, K. M., Dikkes, P., Fujiwara, Y., Seidl, K. J., Sekiguchi, J. M., Rathbun, G. A., Swat, W., Wang, J., Bronson, R. T., Malynn, B. A., Bryans, M., Zhu, C., Chaudhuri, J., Davidson, L., Ferrini, R., Stamato, T., Orkin, S. H., Greenberg, M. E., and Alt, F. W. (1998) Cell 95, 891–902[CrossRef][Medline] [Order article via Infotrieve]
22. Ooi, S. L., Shoemaker, D. D., and Boeke, J. D. (2001) Science 294, 2552–2556[Abstract/Free Full Text]
23. Dai, Y., Kysela, B., Hanakahi, L. A., Manolis, K., Riballo, E., Stumm, M., Harville, T. O., West, S. C., Oettinger, M. A., and Jeggo, P. A. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 2462–2467[Abstract/Free Full Text]
24. Noordzij, J. G., Verkaik, N. S., Hartwig, N. G., de Groot, R., van Gent, D. C., and van Dongen, J. J. (2000) Blood 96, 203–209[Abstract/Free Full Text]
25. Corneo, B., Moshous, D., Gungor, T., Wulffrat, N., Philippet, P., Le Deist, F., Fischer, A., and de Villartay, J. P. (2001) Blood 97, 2772–2776[Abstract/Free Full Text]
26. George, R. A., Lin, K., and Heringa, J. (2005) Nucleic Acids Res. 33, W160–W163[Abstract/Free Full Text]
27. Astrom, S. U., Okamura, S. M., and Rine, J. (1999) Nature 397, 310[CrossRef][Medline] [Order article via Infotrieve]
28. Lee, S. E., Paques, F., Sylvan, J., and Haber, J. E. (1999) Curr. Biol. 9, 767–770[CrossRef][Medline] [Order article via Infotrieve]
29. Clikeman, J. A., Khalsa, G. J., Barton, S. L., and Nickoloff, J. A. (2001) Genetics 157, 579–589[Abstract/Free Full Text]

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				P. Raval, A. N. Kriatchko, S. Kumar, and P. C. Swanson Evidence for Ku70/Ku80 association with full-length RAG1 Nucleic Acids Res., April 1, 2008; 36(6): 2060 - 2072. [Abstract] [Full Text] [PDF]

				P.-Y. Wu, P. Frit, L. Malivert, P. Revy, D. Biard, B. Salles, and P. Calsou Interplay between Cernunnos-XLF and Nonhomologous End-joining Proteins at DNA Ends in the Cell J. Biol. Chem., November 2, 2007; 282(44): 31937 - 31943. [Abstract] [Full Text] [PDF]

				P. Burton, D. J. McBride, J. M. Wilkes, J. D. Barry, and R. McCulloch Ku Heterodimer-Independent End Joining in Trypanosoma brucei Cell Extracts Relies upon Sequence Microhomology Eukaryot. Cell, October 1, 2007; 6(10): 1773 - 1781. [Abstract] [Full Text] [PDF]

				J. Gu, H. Lu, A. G. Tsai, K. Schwarz, and M. R. Lieber Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence Nucleic Acids Res., September 27, 2007; 35(17): 5755 - 5762. [Abstract] [Full Text] [PDF]

				P. Soulas-Sprauel, G. Le Guyader, P. Rivera-Munoz, V. Abramowski, C. Olivier-Martin, C. Goujet-Zalc, P. Charneau, and J.-P. de Villartay Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination J. Exp. Med., July 9, 2007; 204(7): 1717 - 1727. [Abstract] [Full Text] [PDF]

				D. S. F. Biard Untangling the relationships between DNA repair pathways by silencing more than 20 DNA repair genes in human stable clones Nucleic Acids Res., June 28, 2007; 35(11): 3535 - 3550. [Abstract] [Full Text] [PDF]

				H. Lu, U. Pannicke, K. Schwarz, and M. R. Lieber Length-dependent Binding of Human XLF to DNA and Stimulation of XRCC4{middle dot}DNA Ligase IV Activity J. Biol. Chem., April 13, 2007; 282(15): 11155 - 11162. [Abstract] [Full Text] [PDF]

				S. Zha, F. W. Alt, H.-L. Cheng, J. W. Brush, and G. Li Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells PNAS, March 13, 2007; 104(11): 4518 - 4523. [Abstract] [Full Text] [PDF]

				S. D. Carter, S. Iyer, J. Xu, M. J. McEachern, and S. U. Astrom The Role Of Nonhomologous End-Joining Components in Telomere Metabolism in Kluyveromyces lactis Genetics, March 1, 2007; 175(3): 1035 - 1045. [Abstract] [Full Text] [PDF]

				S. Cavero, C. Chahwan, and P. Russell Xlf1 Is Required for DNA Repair by Nonhomologous End Joining in Schizosaccharomyces pombe Genetics, February 1, 2007; 175(2): 963 - 967. [Abstract] [Full Text] [PDF]

				P. Hentges, P. Ahnesorg, R. S. Pitcher, C. K. Bruce, B. Kysela, A. J. Green, J. Bianchi, T. E. Wilson, S. P. Jackson, and A. J. Doherty Evolutionary and Functional Conservation of the DNA Non-homologous End-joining Protein, XLF/Cernunnos J. Biol. Chem., December 8, 2006; 281(49): 37517 - 37526. [Abstract] [Full Text] [PDF]

				S. L. Sawyer and H. S. Malik Eukaryotic Transposable Elements and Genome Evolution Special Feature: Positive selection of yeast nonhomologous end-joining genes and a retrotransposon conflict hypothesis PNAS, November 21, 2006; 103(47): 17614 - 17619. [Abstract] [Full Text] [PDF]

				C. J. Lord, M. D. Garrett, and A. Ashworth Targeting the Double-Strand DNA Break Repair Pathway as a Therapeutic Strategy Clin. Cancer Res., August 1, 2006; 12(15): 4463 - 4468. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Supplemental Data All Versions of this Article: 281/20/13857    most recent C500473200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Callebaut, I. Articles by de Villartay, J.-P. Search for Related Content PubMed PubMed Citation Articles by Callebaut, I. Articles by de Villartay, J.-P. Social Bookmarking                      What's this?