Nonhomologous end joining and V(D)J recombination require an additional factor

Dai, Yan; Kysela, Boris; Hanakahi, Leslyn A.; Manolis, Kostas; Riballo, Enriqueta; Stümm, Markus; Harville, Terry; West, Stephen C.; Oettinger, Marjorie A.; Jeggo, Penelope A.

doi:10.1073/pnas.0437964100

Cited by 164 publications

(126 citation statements)

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“…In p53-deficient backgrounds, the unrepaired programmed DSBs in C-NHEJ-deficient mice participate oncogenic chromosomal translocations and eventually lead to lymphomas (1). XLF mutations cause a progressive lymphocytopenia that is usually less severe than SCID (3,4,8) in human patients. XLF-deficient mice have reduced lymphocyte numbers, but do not exhibit stage-specific blockade (7).…”

mentioning

confidence: 99%

Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development

Liu

Jiang²,

Dubois³

et al. 2012

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

110

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Nonhomologous end joining (NHEJ), a major pathway of DNA double-strand break (DSB) repair, is required during lymphocyte development to resolve the programmed DSBs generated during Variable, Diverse, and Joining [V(D)J] recombination. XRCC4-like factor (XLF) (also called Cernunnos or NHEJ1) is a unique component of the NHEJ pathway. Although germ-line mutations of other NHEJ factors abrogate lymphocyte development and lead to severe combined immunodeficiency (SCID), XLF mutations cause a progressive lymphocytopenia that is generally less severe than SCID. Accordingly, XLF-deficient murine lymphocytes show no measurable defects in V(D)J recombination. We reported earlier that ATM kinase and its substrate histone H2AX are both essential for V(D)J recombination in XLF-deficient lymphocytes, despite moderate role in V(D)J recombination in WT cells. p53-binding protein 1 (53BP1) is another substrate of ATM. 53BP1 deficiency led to small reduction of peripheral lymphocyte number by compromising both synapse and end-joining at modest level during V(D)J recombination. Here, we report that 53BP1/XLF double deficiency blocks lymphocyte development at early progenitor stages, owing to severe defects in end joining during chromosomal V(D)J recombination. The unrepaired DNA ends are rapidly degraded in 53BP1 −/− XLF −/− cells, as reported for H2AX −/− XLF −/− cells, revealing an end protection role for 53BP1 reminiscent of H2AX. In contrast to the early embryonic lethality of H2AX −/− XLF −/− mice, 53BP1 −/− XLF −/− mice are born alive and develop thymic lymphomas with translocations involving the T-cell receptor loci. Together, our findings identify a unique function for 53BP1 in end-joining and tumor suppression.Ataxia-Telangiectasia-Mutated | XRCC4-like factor | classical nonhomologous end joining L ymphocyte development requires the ordered assembly of variable region of antigen receptor genes from individual Variable, Diverse, and Joining gene segments through V(D)J recombination (1). V(D)J recombination is initiated by the RAG endonuclease (RAG), which introduces DNA double-strand breaks (DSBs) between the conserved recombination signal sequence (RSS) and the participating germ-line V, D, or J gene segments (1). RAG cleavage generates two types of DNA ends, the 5′-phosphorylated blunt signal ends (SEs) and the hairpin sealed coding ends (CEs) (1). In the next step, ubiquitously expressed classical nonhomologous end-joining (C-NHEJ) factors directly join the two SEs to form a signal join (SJ), and process (via hairpin opening, de novo synthesis, and loss of nucleotides) and join the two CEs to form a coding join (CJ) (1).There are seven C-NHEJ factors in mammalian cells. Ku70 and Ku80 (or KU86 in human) form heterodimers (KU) that bind DSB ends and, among other functions, recruit and activate other NHEJ factors (2). DNA-bound KU interacts with the DNA-PK catalytic subunit (DNA-PKcs), and together they activate the endonuclease function of Artemis for end processing, including opening hairpin-sealed CEs during V(D)J reco...

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mentioning

confidence: 99%

Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development

Liu

Jiang²,

Dubois³

et al. 2012

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

110

View full text Add to dashboard Cite

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“…Recently developed murine Cernunnos-deficient ES cells present a phenotype similar to that of human deficient cells (increased radiosensitivity, genomic instability, DNA repair defect), except for V(D)J recombination (Zha et al, 2007). Although the efficiency of V(D)J recombination is highly compromised, the fidelity of signal joins is not altered in Cernunnos-deficient ES cells, contrasting with the human situation where more than half of the signal joins are imprecise, with various lengths of nucleotide deletions (Dai et al, 2003;Buck et al, 2006a). The nature of the mutation engineered in ES cells (the deletion of Cernunnos exons 4 and 5 could result in the low level expression of a truncated Cernunnos protein created by an in-frame splicing from exon 3 to exon 6) may partly account for these differences (Zha et al, 2007).…”

Section: Cernunnosmentioning

confidence: 93%

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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“…RS-SCID was described as a phenotype in a number of immunodeficiency patients but identifying the defective gene(s) progressed slowly [52][53][54]. The identification of mutations in DCLRE1C/Artemis was the next genetic defect for RS-SCID to be identified, facilitated by its occurrence within a community of Athabascan America Indians (see below for further details) [55].…”

Section: Xlf/cernunnos Defective Patientsmentioning

confidence: 99%

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

2014

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Double strand break repair V(D)J recombination (Severe) combined immunodeficiency -(S)CID Human syndromes a b s t r a c t DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway in mammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models, since radiation potently induces DSBs. The process of V(D)J recombination functions during the development of the immune response, and involves the introduction and rejoining of programmed DSBs to generate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJ deficiency confers (severe) combined immunodeficiency -(S)CID -due to a failure to carry out V(D)J recombination efficiently. NHEJ also functions in class switch recombination, another step enhancing T and B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patients revealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syndromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have been identified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCID patients frequently display additional characteristics including microcephaly, dysmorphic facial features and growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our current understanding of the underlying biology.

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Nonhomologous end joining and V(D)J recombination require an additional factor

Abstract: DNA nonhomologous end-joining (NHEJ) is

Cited by 164 publications

References 38 publications

Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development

Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development

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

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

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