RAG2 and XLF/Cernunnos Interplay Reveals a Novel Role for the RAG Complex in DNA Repair

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Feb 3

PMID 26833222

Citations 40

Authors

Chloe Lescale

Vincent Abramowski

Marie Bedora-Faure

Valentine Murigneux

Gabriella Vera

David B Roth

Patrick Revy

Jean-Pierre de Villartay

Ludovic Deriano

Affiliations

Soon will be listed here.

Abstract

XRCC4-like factor (XLF) functions in classical non-homologous end-joining (cNHEJ) but is dispensable for the repair of DNA double-strand breaks (DSBs) generated during V(D)J recombination. A long-standing hypothesis proposes that, in addition to its canonical nuclease activity, the RAG1/2 proteins participate in the DNA repair phase of V(D)J recombination. Here we show that in the context of RAG2 lacking the C-terminus domain (Rag2(c/c) mice), XLF deficiency leads to a profound lymphopenia associated with a severe defect in V(D)J recombination and, in the absence of p53, increased genomic instability at V(D)J sites. In addition, Rag2(c/c) XLF(-/-) p53(-/-) mice develop aggressive pro-B cell lymphomas bearing complex chromosomal translocations and gene amplifications involving Igh and c-myc/pvt1 loci. Our results reveal an unanticipated functional interplay between the RAG complex and XLF in repairing RAG-induced DSBs and maintaining genome integrity during antigen receptor gene assembly.

Citing Articles

Phosphorylation of DNA-PKcs at the S2056 cluster ensures efficient and productive lymphocyte development in XLF-deficient mice.

Zhu Y, Jiang W, Lee B, Li A, Gershik S, Zha S Proc Natl Acad Sci U S A. 2023; 120(25):e2221894120.

PMID: 37307443 PMC: 10288554. DOI: 10.1073/pnas.2221894120.

SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination.

Vincendeau E, Wei W, Zhang X, Planchais C, Yu W, Lenden-Hasse H Nat Commun. 2022; 13(1):3707.

PMID: 35764636 PMC: 9240092. DOI: 10.1038/s41467-022-31287-3.

V(D)J Recombination: Recent Insights in Formation of the Recombinase Complex and Recruitment of DNA Repair Machinery.

Christie S, Fijen C, Rothenberg E Front Cell Dev Biol. 2022; 10:886718.

PMID: 35573672 PMC: 9099191. DOI: 10.3389/fcell.2022.886718.

Role of Paralogue of XRCC4 and XLF in DNA Damage Repair and Cancer Development.

Tang J, Li Z, Wu Q, Irfan M, Li W, Liu X Front Immunol. 2022; 13:852453.

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Assessing DNA Damage Responses Using B Lymphocyte Cultures.

Johnston R, White L, Bednarski J Methods Mol Biol. 2022; 2444:69-80.

PMID: 35290632 DOI: 10.1007/978-1-0716-2063-2_5.

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