Faculty Opinions recommendation of A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination.

2013 ◽  
Author(s):  
Craig Bassing
Keyword(s):  
Class Switch Recombination ◽  
Nonhomologous End Joining ◽  
Regulatory Role ◽  
End Joining ◽  
Immunoglobulin Class ◽  
Class Switch

scholarly journals Involvement of Artemis in nonhomologous end-joining during immunoglobulin class switch recombination

2008 ◽  
Vol 205 (13) ◽  
pp. 3031-3040 ◽  
Author(s):  
Likun Du ◽  
Mirjam van der Burg ◽  
Sergey W. Popov ◽  
Ashwin Kotnis ◽  
Jacques J.M. van Dongen ◽  
...  
Keyword(s):  
Class Switch Recombination ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Igg Subclass ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Immunoglobulin Class ◽  
Class Switch ◽  
Human B Cells

DNA double-strand breaks (DSBs) introduced in the switch (S) regions are intermediates during immunoglobulin class switch recombination (CSR). These breaks are subsequently recognized, processed, and joined, leading to recombination of the two S regions. Nonhomologous end-joining (NHEJ) is believed to be the principle mechanism involved in DSB repair during CSR. One important component in NHEJ, Artemis, has however been considered to be dispensable for efficient CSR. In this study, we have characterized the S recombinational junctions from Artemis-deficient human B cells. Sμ–Sα junctions could be amplified from all patients tested and were characterized by a complete lack of “direct” end-joining and a remarkable shift in the use of an alternative, microhomology-based end-joining pathway. Sμ–Sγ junctions could only be amplified from one patient who carries “hypomorphic” mutations. Although these Sμ–Sγ junctions appear to be normal, a significant increase of an unusual type of sequential switching from immunoglobulin (Ig)M, through one IgG subclass, to a different IgG subclass was observed, and the Sγ–Sγ junctions showed long microhomologies. Thus, when the function of Artemis is impaired, varying modes of CSR junction resolution may be used for different S regions. Our findings strongly link Artemis to the predominant NHEJ pathway during CSR.

scholarly journals A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination

2013 ◽  
Vol 210 (12) ◽  
pp. 2503-2513 ◽  
Author(s):  
Elin Enervald ◽  
Likun Du ◽  
Torkild Visnes ◽  
Andrea Björkman ◽  
Emma Lindgren ◽  
...  
Keyword(s):  
Class Switch Recombination ◽  
Nonhomologous End Joining ◽  
Loss Of Function ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Gene Encoding ◽  
Immunoglobulin Class ◽  
Cellular Processes ◽  
Class Switch ◽  
Cornelia De Lange

DNA double strand breaks (DSBs) are mainly repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ). These breaks pose severe threats to genome integrity but can also be necessary intermediates of normal cellular processes such as immunoglobulin class switch recombination (CSR). During CSR, DSBs are produced in the G1 phase of the cell cycle and are repaired by the classical NHEJ machinery. By studying B lymphocytes derived from patients with Cornelia de Lange Syndrome, we observed a strong correlation between heterozygous loss-of-function mutations in the gene encoding the cohesin loading protein NIPBL and a shift toward the use of an alternative, microhomology-based end joining during CSR. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Association of NIPBL deficiency and impaired NHEJ was also observed in a plasmid-based end-joining assay and a yeast model system. Our results suggest that NIPBL plays an important and evolutionarily conserved role in NHEJ, in addition to its canonical function in sister chromatid cohesion and its recently suggested function in HR.

scholarly journals The cohesin complex regulates immunoglobulin class switch recombination

2013 ◽  
Vol 210 (12) ◽  
pp. 2495-2502 ◽  
Author(s):  
Anne-Sophie Thomas-Claudepierre ◽  
Ebe Schiavo ◽  
Vincent Heyer ◽  
Marjorie Fournier ◽  
Adeline Page ◽  
...  
Keyword(s):  
Cytidine Deaminase ◽  
Class Switch Recombination ◽  
Nonhomologous End Joining ◽  
Cohesin Complex ◽  
Dna Breaks ◽  
End Joining ◽  
Regulatory Subunits ◽  
Class Switch ◽  
Chromatid Cohesion ◽  
Switch Regions

Immunoglobulin (Ig) class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation-induced cytidine deaminase (AID) to switch regions and by the subsequent generation of double-stranded DNA breaks (DSBs). These DNA breaks are ultimately resolved through the nonhomologous end joining (NHEJ) pathway. We show that during CSR, AID associates with subunits of cohesin, a complex previously implicated in sister chromatid cohesion, DNA repair, and the formation of DNA loops between enhancers and promoters. Furthermore, we implicate the cohesin complex in the mechanism of CSR by showing that cohesin is dynamically recruited to the Sμ-Cμ region of the IgH locus during CSR and that knockdown of cohesin or its regulatory subunits results in impaired CSR and increased usage of microhomology-based end joining.

scholarly journals An in vivo study of the impact of deficiency in the DNA repair proteins PAXX and XLF on development and maturation of the hemolymphoid system

2020 ◽  
Vol 295 (8) ◽  
pp. 2398-2406 ◽  
Author(s):  
Stefania Musilli ◽  
Vincent Abramowski ◽  
Benoit Roch ◽  
Jean-Pierre de Villartay
Keyword(s):  
Class Switch Recombination ◽  
Adaptive Immune System ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
Hematopoietic Progenitors ◽  
End Joining ◽  
Class Switch ◽  
A Genome ◽  
The Impact

Repair of DNA double-strand breaks by the nonhomologous end joining pathway is central for proper development of the adaptive immune system. This repair pathway involves eight factors, including XRCC4-like factor (XLF)/Cernunnos and the paralog of XRCC4 and XLF, PAXX nonhomologous end joining factor (PAXX). Xlf−/− and Paxx−/− mice are viable and exhibit only a mild immunophenotype. However, mice lacking both PAXX and XLF are embryonic lethal because postmitotic neurons undergo massive apoptosis in embryos. To decipher the roles of PAXX and XLF in both variable, diversity, and joining recombination and immunoglobulin class switch recombination, here, using Cre/lox-specific deletion to prevent double-KO embryonic lethality, we developed two mouse models of a conditional Xlf KO in a Paxx−/− background. Cre expressed under control of the iVav or CD21 promoter enabled Xlf deletion in early hematopoietic progenitors and splenic mature B cells, respectively. We demonstrate the XLF and PAXX interplay during variable, diversity, and joining recombination in vivo but not during class switch recombination, for which PAXX appeared to be fully dispensable. Xlf/Paxx double KO in hematopoietic progenitors resulted in a shorter lifespan associated with onset of thymic lymphomas, revealing a genome caretaking function of XLF/PAXX.

scholarly journals Robust immunoglobulin class switch recombination and end joining inParp9-deficient mice

2017 ◽  
Vol 47 (4) ◽  
pp. 665-676 ◽  
Author(s):  
Isabelle Robert ◽  
Léa Gaudot ◽  
José Yélamos ◽  
Aurélia Noll ◽  
Heng-Kuan Wong ◽  
...  
Keyword(s):  
Class Switch Recombination ◽  
End Joining ◽  
Immunoglobulin Class ◽  
Class Switch ◽  
Deficient Mice

scholarly journals Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome

2020 ◽  
Vol 217 (11) ◽  
Author(s):  
Angela Helfricht ◽  
Peter E. Thijssen ◽  
Magdalena B. Rother ◽  
Rashmi G. Shah ◽  
Likun Du ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Class Switch Recombination ◽  
Nonhomologous End Joining ◽  
Dna Breaks ◽  
End Joining ◽  
Immunoglobulin Production ◽  
Icf Syndrome ◽  
Class Switch ◽  
Centromeric Instability ◽  
Gene Defects

The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome.

scholarly journals Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4

2010 ◽  
Vol 207 (2) ◽  
pp. 417-427 ◽  
Author(s):  
Cristian Boboila ◽  
Catherine Yan ◽  
Duane R. Wesemann ◽  
Mila Jankovic ◽  
Jing H. Wang ◽  
...  
Keyword(s):  
B Cells ◽  
Class Switch Recombination ◽  
Strand Break ◽  
Nonhomologous End Joining ◽  
Dna Ligase ◽  
End Joining ◽  
Dsb Repair ◽  
Class Switch ◽  
Dna Double Strand Break ◽  
Alternative End Joining

The classical nonhomologous end-joining (C-NHEJ) DNA double-strand break (DSB) repair pathway employs the Ku70/80 complex (Ku) for DSB recognition and the XRCC4/DNA ligase 4 (Lig4) complex for ligation. During IgH class switch recombination (CSR) in B lymphocytes, switch (S) region DSBs are joined by C-NHEJ to form junctions either with short microhomologies (MHs; “MH-mediated” joins) or no homologies (“direct” joins). In the absence of XRCC4 or Lig4, substantial CSR occurs via “alternative” end-joining (A-EJ) that generates largely MH-mediated joins. Because upstream C-NHEJ components remain in XRCC4- or Lig4-deficient B cells, residual CSR might be catalyzed by C-NHEJ using a different ligase. To address this, we have assayed for CSR in B cells deficient for Ku70, Ku80, or both Ku70 and Lig4. Ku70- or Ku80-deficient B cells have reduced, but still substantial, CSR. Strikingly, B cells deficient for both Ku plus Lig4 undergo CSR similarly to Ku-deficient B cells, firmly demonstrating that an A-EJ pathway distinct from C-NHEJ can catalyze CSR end-joining. Ku-deficient or Ku- plus Lig4-deficient B cells are also biased toward MH-mediated CSR joins; but, in contrast to XRCC4- or Lig4-deficient B cells, generate substantial numbers of direct CSR joins. Our findings suggest that more than one form of A-EJ can function in CSR.

scholarly journals Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination

2009 ◽  
Vol 206 (5) ◽  
pp. 1047-1056 ◽  
Author(s):  
Isabelle Robert ◽  
Françoise Dantzer ◽  
Bernardo Reina-San-Martin
Keyword(s):  
Dna Damage ◽  
Cytidine Deaminase ◽  
Class Switch Recombination ◽  
Dependent Manner ◽  
Dna Breaks ◽  
End Joining ◽  
Immunoglobulin Class ◽  
Class Switch ◽  
Switch Regions ◽  
Alternative Nhej

Immunoglobulin class switch recombination (CSR) is initiated by DNA breaks triggered by activation-induced cytidine deaminase (AID). These breaks activate DNA damage response proteins to promote appropriate repair and long-range recombination. Aberrant processing of these breaks, however, results in decreased CSR and/or increased frequency of illegitimate recombination between the immunoglobulin heavy chain locus and oncogenes like c-myc. Here, we have examined the contribution of the DNA damage sensors Parp1 and Parp2 in the resolution of AID-induced DNA breaks during CSR. We find that although Parp enzymatic activity is induced in an AID-dependent manner during CSR, neither Parp1 nor Parp2 are required for CSR. We find however, that Parp1 favors repair of switch regions through a microhomology-mediated pathway and that Parp2 actively suppresses IgH/c-myc translocations. Thus, we define Parp1 as facilitating alternative end-joining and Parp2 as a novel translocation suppressor during CSR.

scholarly journals Regulation of DNA End Joining, Resection, and Immunoglobulin Class Switch Recombination by 53BP1

2011 ◽  
Vol 42 (3) ◽  
pp. 319-329 ◽  
Author(s):  
Anne Bothmer ◽  
Davide F. Robbiani ◽  
Michela Di Virgilio ◽  
Samuel F. Bunting ◽  
Isaac A. Klein ◽  
...  
Keyword(s):  
Class Switch Recombination ◽  
End Joining ◽  
Immunoglobulin Class ◽  
Class Switch
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