Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination

Soulas-Sprauel, Pauline; Guyader, Gwenaël Le; Rivera-Munoz, Paola; Abramowski, Vincent; Olivier-Martin, Christelle; Goujet‐Zalc, C.; Charneau, Pierre; Villartay, Jean‐Pierre de

doi:10.1084/jem.20070255

Cited by 131 publications

(131 citation statements)

References 53 publications

(99 reference statements)

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“…These data are highly consistent with the recent in vivo description of significant CSR efficiency in xrcc4-or Lig4-defective mouse B cells by an alternative pathway, using microhomologies and robust XRCC4-alternative V(D)J recombination (17,18,24). These results indicate that the XRCC4-alt pathway is not specific to differentiated, specialized cells (B cells), or to a particular process (CSR), but more generally acts in DSB repair and in different cell types.…”

Section: Discussionsupporting

confidence: 79%

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Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends

Guirouilh‐Barbat

Rass

Plo

et al. 2007

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

152

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XRCC4-null mice have a more severe phenotype than KU80-null mice. Here, we address whether this difference in phenotype is connected to nonhomologous end-joining (NHEJ). We used intrachromosomal substrates to monitor NHEJ of two distal doublestrand breaks (DSBs) targeted by I-SceI, in living cells. In xrcc4-defective XR-1 cells, a residual but significant end-joining process exists, which primarily uses microhomologies distal from the DSB. However, NHEJ efficiency was strongly reduced in xrcc4-defective XR-1 cells versus complemented cells, contrasting with KU-deficient xrs6 cells, which showed levels of end-joining similar to those of complemented cells. Nevertheless, sequence analysis of the repair junctions indicated that the accuracy of end-joining was strongly affected in both xrcc4-deficient and KU-deficient cells. More specifically, these data showed that the KU80/XRCC4 pathway is conservative and not intrinsically error-prone but can accommodate non-fully complementary ends at the cost of limited mutagenesis.double-strand break repair ͉ genome rearrangements D NA double-strand breaks (DSBs) are harmful lesions generated by a variety of endogenous or exogenous stresses, potentially leading to genomic rearrangement. Nonhomologous endjoining (NHEJ) is a prominent pathway for DSB repair (1). Canonical NHEJ involves the successive intervention of the KU80-KU70 heterodimer, DNA-PKcs-Artemis, and, finally, ligase IV (Lig4) associated with its cofactors XRCC4 and Cernunnos/Xlf (2, 3). KU-independent NHEJ (KU-alt) has been described in vitro in both acellular extracts and cultured cells (1, 4-6).Alternative, XRCC4-independent DSB repair pathways (XRCC4-alt) have also been described, using episomic plasmid in cultured cells, using pulse field gel electrophoresis, or in in vitro biochemical experiments (5-10). One hypothesis could propose that XRCC4 and KU are implicated in the same canonical NHEJ pathway, whereas the alternate pathway is independent of both KU and XRCC4. However, in transgenic mice, the inactivation of XRCC4 or Lig4 results in a more severe phenotype than the inactivation of KU (11), suggesting that XRCC4 might have an additional essential function; however, studies show that XRCC4 and Lig4 do not have roles outside of NHEJ, whereas in contrast, KU acts in other processes such as transcription, apoptosis, and responses to the cell microenvironment (12)(13)(14).Alternatively, these varying phenotypes in mice may actually result from differences in DSB repair efficiencies, indicating that defects in XRCC4 might be more deleterious for DSB repair than defects in KU. What challenges this hypothesis, however, is that substantial class switch recombination (CSR) has recently been shown to occur in mouse B cells without XRCC4, whereas no CSR was recorded in cells devoid of KU (15-18).The relative contributions of XRCC4 and KU80 versus the XRCC4-alt and KU-alt pathways, respectively, to DSB repair remain unclear in wild-type cells. Contrasting results were obtained in living cells, using an episomic plasm...

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Section: Discussionsupporting

confidence: 79%

“…What challenges this hypothesis, however, is that substantial class switch recombination (CSR) has recently been shown to occur in mouse B cells without XRCC4, whereas no CSR was recorded in cells devoid of KU (15)(16)(17)(18).…”

mentioning

confidence: 83%

Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends

Guirouilh‐Barbat

Rass

Plo

et al. 2007

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

152

183

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“…XRCC4 and DNA-ligase IV are two factors without known function outside DNA end joining during NHEJ, but the KO of these two factors is embryonic lethal [3], which adds another difficulty for their study during CSR. A very recent study has employed B cell-specific XRCC4 inactivation to show that CSR is reduced, yet not fully abrogated, in the absence of XRCC4 [55]. The CSR SlSc1 junctions in B cells from these animals demonstrated a slight increase in microhomology usage, reminiscent of a similar observation in B cells from human patients harboring various DNA repair defects, including DNA-ligase IV deficiency [56][57][58].…”

Section: Nhej and Csrmentioning

confidence: 84%

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

et al. 2007

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B and T lymphocytes are exposed to various genotoxic stresses during their life, which originate from programmed molecular mechanisms during their development and maturation or are secondary to cellular metabolism during acute phases of cell proliferation and activation during immune responses. How lymphocytes handle these multiple genomic assault has become a focus of interest over the years, perhaps beginning with the identification of the murine scid model in the early 80s when it was recognized that DNA repair deficiencies had profound consequences on the immune system. In this respect, the immune system represents an ideal model to study DNA damage responses (DDR) and the survey of immune deficiency conditions in humans or the development of specific animal models provided many major contributions in our understanding of the various biochemical pathways at play during DDR in general. Although the role of DNA repair in the early phases of B and T cell development has been analyzed thoroughly, the role of these functions in various aspects of the mature immune system (homeostasis, immunological memory, ageing) is less well understood. Lastly, the analysis of DNA repair in the immune system has provided many insights in the more general understanding of cancer. IntroductionAll living organisms are exposed to endogenous and environmental genotoxic stresses causing DNA injuries. Among these lesions, DNA double-strand breaks (DNAdsb) are considered as the most harmful. Unrepaired DNA damage can lead to mutation, cancer, or cell death. Several cellular responses are triggered, in what is called the DNA damage response (DDR), to handle DNA lesions (Fig. 1). The purpose of this review is not to go in the depth of the various biochemical pathways that constitute the DDR, as this aspect has been covered elsewhere [1], but rather to discuss, in an historical way, how the immune system depends on these pathways on one hand, and how studies of the immune system have been instrumental in the better understanding of some of these pathways, in particular the non-homologous end joining (NHEJ) pathway. Indeed, the immune system is the place of many genotoxic stresses that happen at various time points during the development and maturation of lymphocytes (Fig. 2). These DNA We discuss here the links that exist between the immune system and the DDR with the standpoint of the lymphocyte lifespan, from birth to ageing, and discuss the consequences of DNA repair defects on the integrity of the immune system. Development of the immune system V(D)J recombinationB and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the BCR and TCR, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Fig. 3), which assembles previously scattered variable (V), diversity (D), and joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism [2]. The reaction is initiated by the lymphoid-specific factors Rag1 and Rag2, which specifically...

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“…XRCC4 and DNA-ligaseIV are the only factors without a known function apart from NHEJ, but the corresponding KO models are embryonic lethal, which does not facilitate the task of their study in CSR. To overcome this viability impact as well as the block in B-and T-cell maturation in XRCC4 KO mice, two laboratories recently developed XRCC4 and DNALigaseIV conditional gene targeting approaches through the use of LoxP/Cre technology (Soulas-Sprauel et al, 2007;Yan et al, 2007). In these studies, the Cre expression is under the regulation of the B-cell-specific CD21 promoter, thus restraining the gene targeting in mature B cells.…”

Section: Nhej and Csrmentioning

confidence: 99%

“…Perhaps most importantly, this last study demonstrates that alternative NHEJ is quite robust and can even participate in DNA end-joining in NHEJ-proficient cells, which further raises the question of regulation among the various DNA repair pathways. In the case of CSR, the synapsis of DNA ends being probably maintained by the DDR complex (Ooi et al, 2001), this complex also recruits the DNA end-joining machinery and one can assume that NHEJ is preferred over other pathways but can easily be replaced in case of faulty NHEJ, as shown with XRCC4 conditional KO mice (Soulas-Sprauel et al, 2007;Yan et al, 2007), given the homology that exists between S regions. The DNA repair phase of CSR is not presently fully understood and other factors have yet to be identified (Peron et al, 2007).…”

Section: Nhej and Csrmentioning

confidence: 99%

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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Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination

Cited by 131 publications

References 53 publications

Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends

Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

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

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