title: DNA Replication Origins in Immunoglobulin Switch Regions Regulate Class Switch Recombination in an R-Loop-Dependent Manner.
abstract: Class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) locus generates antibody isotypes. CSR depends on double-strand breaks (DSBs) induced by activation-induced cytidine deaminase (AID). Although DSB formation and repair machineries are active in G1 phase, efficient CSR is dependent on cell proliferation and S phase entry; however, the underlying mechanisms are obscure. Here, we show that efficient CSR requires the replicative helicase, the Mcm complex. Mcm proteins are enriched at IgH switch regions during CSR, leading to assembly of facultative replication origins that require Mcm helicase function for productive CSR. Assembly of CSR-associated origins is facilitated by R loops and promotes the physical proximity (synapsis) of recombining switch regions, which is reduced by R loop inhibition or Mcm complex depletion. Thus, R loops contribute to replication origin specification that promotes DSB resolution in CSR. This suggests a mechanism for the dependence of CSR on S phase and cell division.
authors.affiliation: Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, Vienna 1030, Austria.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Wiedemann
authors.affiliation: Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, Vienna 1030, Austria.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Peycheva
authors.affiliation: Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, Vienna 1030, Austria. Electronic address: rushad.pavri@imp.ac.at.
authors.forename: Rushad
authors.initials: R
authors.lastname: Pavri
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics* / Q000276:immunology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics / Q000276:immunology; D004261:DNA Replication / Q000235:genetics / Q000276:immunology*; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology*; D051379:Mice; D064110:Minichromosome Maintenance Proteins / Q000235:genetics* / Q000276:immunology; D018741:Replication Origin / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000906:Antibodies; D007143:Immunoglobulin Heavy Chains; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D064110:Minichromosome Maintenance Proteins
keywords: DNA replication; R loops; class switch recombination