title: A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination.
abstract: 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.
authors.affiliation: Department of Cell and Molecular Biology, 2 Department of Laboratory Medicine, 3 Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Enervald
authors.forename: Likun
authors.initials: L
authors.lastname: Du
authors.forename: Torkild
authors.initials: T
authors.lastname: Visnes
authors.forename: Andrea
authors.initials: A
authors.lastname: Björkman
authors.forename: Emma
authors.initials: E
authors.lastname: Lindgren
authors.forename: Josephine
authors.initials: J
authors.lastname: Wincent
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.forename: Juan
authors.initials: J
authors.lastname: Pie
authors.forename: Beatriz
authors.initials: B
authors.lastname: Puisac
authors.forename: Noel Fcc
authors.initials: NF
authors.lastname: de Miranda
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schoumans
authors.forename: Lena
authors.initials: L
authors.lastname: Ström
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
mesh_terms: D000293:Adolescent; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D003635:De Lange Syndrome / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D017578:Immunoglobulin Class Switching; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D000097722:Cohesins; C487465:NIPBL protein, human; C498301:TP53BP1 protein, human