title: The hSSB1 orthologue Obfc2b is essential for skeletogenesis but dispensable for the DNA damage response in vivo.
abstract: Human single-stranded DNA-binding protein 1 (hSSB1), encoded by OBFC2B, was recently characterized as an essential factor for the initiation of DNA damage checkpoints and the maintenance of genomic stability. Here, we report that loss of Obfc2b in mice results in perinatal lethality characterized by growth delay and skeletal abnormalities. These abnormalities are associated with accumulation of γH2ax, apoptosis and defective pre-cartilage condensation, which is essential for normal bone formation. However, deficiency of Obfc2b does not affect the initiation of DNA damage checkpoints, Atm activation, or the maintenance of genomic stability in B lymphocytes and primary fibroblasts. Loss of Obfc2b results in increased expression of its homologue Obfc2a (hSSB2). In contrast to Obfc2b deficiency, depletion of Obfc2a in fibroblasts results in impaired proliferation, accumulation of γH2ax and increased genomic instability. Thus, the hSSB1 orthologue Obfc2b has a unique function during embryogenesis limited to cell types that contribute to bone formation. While being dispensable in most other cell lineages, its absence leads to a compensatory increase in Obfc2a protein, a homologue required for the maintenance of genomic integrity.
authors.affiliation: Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA. nfeldhahn@rockefeller.edu
authors.forename: Niklas
authors.initials: N
authors.lastname: Feldhahn
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Davide F
authors.initials: DF
authors.lastname: Robbiani
authors.forename: Elsa
authors.initials: E
authors.lastname: Callen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Deroubaix
authors.forename: Licia
authors.initials: L
authors.lastname: Selleri
authors.forename: Andre
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D001842:Bone and Bones / Q000002:abnormalities / Q000196:embryology; D002455:Cell Division; D019902:Chondrocytes / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D016158:Genes, p53; D006657:Histones / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000002:abnormalities; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D009928:Organ Specificity; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D024101:Mitochondrial Proteins; C577279:SSBP1 protein, mouse; C504092:Ssbp2 protein, mouse; C475961:gamma-H2AX protein, mouse