Specific Roles of XRCC4 Paralogs PAXX and XLF during V(D)J Recombination.
Paralog of XRCC4 and XLF (PAXX) is a member of the XRCC4 superfamily and plays a role in nonhomologous end-joining (NHEJ), a DNA repair pathway critical for lymphocyte antigen receptor gene assembly. Here, we find that the functions of PAXX and XLF in V(D)J recombination are masked by redundant joining activities. Thus, combined PAXX and XLF deficiency leads to an inability to join RAG-cleaved DNA ends. Additionally, we demonstrate that PAXX function in V(D)J recombination depends on its interaction with Ku. Importantly, we show that, unlike XLF, the role of PAXX during the repair of DNA breaks does not overlap with ATM and the RAG complex. Our findings illuminate the role of PAXX in V(D)J recombination and support a model in which PAXX and XLF function during NHEJ repair of DNA breaks, whereas XLF, the RAG complex, and the ATM-dependent DNA damage response promote end joining by stabilizing DNA ends.
Departments of Immunology and Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
Chloé
C
Lescale
Departments of Immunology and Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
Hélène
H
Lenden Hasse
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Andrew N
AN
Blackford
The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Maintenance of Genome Stability, Genome Campus, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Gabriel
G
Balmus
Departments of Immunology and Genomes and Genetics, Institut Pasteur, 75015 Paris, France; Cellule Pasteur, University of Paris René Descartes, Sorbonne Paris Cité, Paris 75015, France.
Joy J
JJ
Bianchi
Departments of Immunology and Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
Wei
W
Yu
Departments of Immunology and Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
Léa
L
Bacoccina
Departments of Immunology and Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
Angélique
A
Jarade
Departments of Immunology and Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
Christophe
C
Clouin
The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Rohan
R
Sivapalan
Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM-U964, CNRS-UMR7104, University of Strasbourg, 67400 Illkirch, France.
Bernardo
B
Reina-San-Martin
The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Maintenance of Genome Stability, Genome Campus, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Stephen P
SP
Jackson
Departments of Immunology and Genomes and Genetics, Institut Pasteur, 75015 Paris, France. Electronic address: ludovic.deriano@pasteur.fr.
Ludovic
L
Deriano
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D064113:CRISPR-Cas Systems / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D017353:Gene Deletion; D000072669:Gene Editing; D015322:Gene Rearrangement, B-Lymphocyte; D007136:Immunoglobulins / Q000235:genetics; D000072200:Ku Autoantigen / Q000378:metabolism; D008954:Models, Biological; D016374:Oncogene Proteins v-abl / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D060152:V(D)J Recombination / Q000235:genetics*
D004268:DNA-Binding Proteins; C014609:IgK; D007136:Immunoglobulins; D016374:Oncogene Proteins v-abl; D064007:Ataxia Telangiectasia Mutated Proteins; D000072200:Ku Autoantigen; D045643:DNA Repair Enzymes
DNA repair; NHEJ; PAXX; V(D)J recombination; XLF; XRCC4