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

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 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 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 Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells

2015 ◽  
Vol 112 (7) ◽  
pp. 2157-2162 ◽  
Author(s):  
Andrea Björkman ◽  
Per Qvist ◽  
Likun Du ◽  
Margarita Bartish ◽  
Apostolos Zaravinos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
B Cells ◽  
Class Switch Recombination ◽  
Cancer Type ◽  
End Joining ◽  
Immunoglobulin Class ◽  
Class Switch ◽  
Human B Cells ◽  
Breast Cancer Type

Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1’s function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.

scholarly journals Impaired induction of DNA lesions during immunoglobulin class-switch recombination in humans influences end-joining repair

2010 ◽  
Vol 107 (51) ◽  
pp. 22225-22230 ◽  
Author(s):  
S. Kracker ◽  
K. Imai ◽  
P. Gardes ◽  
H. D. Ochs ◽  
A. Fischer ◽  
...  
Keyword(s):  
Class Switch Recombination ◽  
Dna Lesions ◽  
End Joining ◽  
Immunoglobulin Class ◽  
Class Switch

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.

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