title: Mechanism of DNA resection during intrachromosomal recombination and immunoglobulin class switching.
abstract: DNA double-strand breaks (DSBs) are byproducts of normal cellular metabolism and obligate intermediates in antigen receptor diversification reactions. These lesions are potentially dangerous because they can lead to deletion of genetic material or chromosome translocation. The chromatin-binding protein 53BP1 and the histone variant H2AX are required for efficient class switch (CSR) and V(D)J recombination in part because they protect DNA ends from resection and thereby favor nonhomologous end joining (NHEJ). Here, we examine the mechanism of DNA end resection in primary B cells. We find that resection depends on both CtBP-interacting protein (CtIP, Rbbp8) and exonuclease 1 (Exo1). Inhibition of CtIP partially rescues the CSR defect in 53BP1- and H2AX-deficient lymphocytes, as does interference with the RecQ helicases Bloom (Blm) and Werner (Wrn). We conclude that CtIP, Exo1, and RecQ helicases contribute to the metabolism of DNA ends during DSB repair in B lymphocytes and that minimizing resection favors efficient CSR.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Bothmer
authors.forename: Philipp C
authors.initials: PC
authors.lastname: Rommel
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.forename: Federica
authors.initials: F
authors.lastname: Polato
authors.forename: Colleen R
authors.initials: CR
authors.lastname: Reczek
authors.forename: Matthias F
authors.initials: MF
authors.lastname: Muellenbeck
authors.forename: Sonja
authors.initials: S
authors.lastname: Schaetzlein
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Phang-Lang
authors.initials: PL
authors.lastname: Chen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brosh
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Richard
authors.initials: R
authors.lastname: Baer
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: Davide F
authors.initials: DF
authors.lastname: Robbiani
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000235:genetics* / Q000378:metabolism; D000076228:MRE11 Homologue Protein; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1; D060152:V(D)J Recombination; D000071657:Werner Syndrome Helicase
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases; D006657:Histones; D007132:Immunoglobulin Isotypes; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins; D053484:RecQ Helicases; D000071857:Tumor Suppressor p53-Binding Protein 1; D000071657:Werner Syndrome Helicase; C501070:RBBP8 protein, mouse; C512689:Mre11a protein, mouse; C498302:Trp53bp1 protein, mouse; C028450:exodeoxyribonuclease I; C097151:Bloom syndrome protein; C499253:Wrn protein, mouse; C475961:gamma-H2AX protein, mouse