Essential Developmental, Genomic Stability, and Tumour Suppressor Functions of the Mouse Orthologue of hSSB1/NABP2

Single-stranded DNA binding proteins (SSBs) regulate multiple DNA transactions, including replication, transcription, and repair. We recently identified SSB1 as a novel protein critical for the initiation of ATM signaling and DNA double-strand break repair by homologous recombination. Here we report that germline Ssb1−/− embryos die at birth from respiratory failure due to severe rib cage malformation and impaired alveolar development, coupled with additional skeletal defects. Unexpectedly, Ssb1 −/− fibroblasts did not exhibit defects in Atm signaling or γ-H2ax focus kinetics in response to ionizing radiation (IR), and B-cell specific deletion of Ssb1 did not affect class-switch recombination in vitro. However, conditional deletion of Ssb1 in adult mice led to increased cancer susceptibility with broad tumour spectrum, impaired male fertility with testicular degeneration, and increased radiosensitivity and IR–induced chromosome breaks in vivo. Collectively, these results demonstrate essential roles of Ssb1 in embryogenesis, spermatogenesis, and genome stability in vivo.

[1]  M. Nussenzweig,et al.  The hSSB1 orthologue Obfc2b is essential for skeletogenesis but dispensable for the DNA damage response in vivo , 2012, The EMBO journal.

[2]  J. Kim Dale,et al.  Somitogenesis , 2012, Development.

[3]  E. Mackie,et al.  The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification. , 2011, The Journal of endocrinology.

[4]  X. Wang,et al.  SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. , 2011, Cancer cell.

[5]  M. Nyegaard,et al.  CtIP Mutations Cause Seckel and Jawad Syndromes , 2011, PLoS genetics.

[6]  T. Franz-Odendaal.  Induction and patterning of intramembranous bone. , 2011, Frontiers in bioscience.

[7]  K. Khanna,et al.  ATM protein kinase: the linchpin of cellular defenses to stress , 2011, Cellular and Molecular Life Sciences.

[8]  S. Hooper,et al.  cAMP Response Element Binding Protein Is Required for Differentiation of Respiratory Epithelium during Murine Development , 2011, PloS one.

[9]  M. F. White,et al.  hSSB1 interacts directly with the MRN complex stimulating its recruitment to DNA double-strand breaks and its endo-nuclease activity , 2011, Nucleic acids research.

[10]  Y. Taniguchi,et al.  Dual Functions of ASCIZ in the DNA Base Damage Response and Pulmonary Organogenesis , 2010, PLoS genetics.

[11]  M. Bhasin,et al.  CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells , 2010, Development.

[12]  Stephen J. Bruce,et al.  Inactivation of Patched1 in the Mouse Limb Has Novel Inhibitory Effects on the Chondrogenic Program* , 2010, The Journal of Biological Chemistry.

[13]  D. Durocher,et al.  Rnf8 deficiency impairs class switch recombination, spermatogenesis, and genomic integrity and predisposes for cancer , 2010, The Journal of experimental medicine.

[14]  M. Jasin,et al.  Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis , 2010, Nature Reviews Molecular Cell Biology.

[15]  N. Tommerup,et al.  Craniosynostosis‐microcephaly with chromosomal breakage and other abnormalities is caused by a truncating MCPH1 mutation and is allelic to premature chromosomal condensation syndrome and primary autosomal recessive microcephaly type 1 , 2010, American journal of medical genetics. Part A.

[16]  G. Peng,et al.  BRIT1/MCPH1 Is Essential for Mitotic and Meiotic Recombination DNA Repair and Maintaining Genomic Stability in Mice , 2010, PLoS genetics.

[17]  M. Pagano,et al.  INTS3 controls the hSSB1-mediated DNA damage response , 2009, The Journal of cell biology.

[18]  Xiaochun Yu,et al.  Integrator3, a Partner of Single-stranded DNA-binding Protein 1, Participates in the DNA Damage Response* , 2009, The Journal of Biological Chemistry.

[19]  Junjie Chen,et al.  SOSS complexes participate in the maintenance of genomic stability. , 2009, Molecular cell.

[20]  T. Pandita,et al.  hSSB1 and hSSB2 Form Similar Multiprotein Complexes That Participate in DNA Damage Response , 2009, The Journal of Biological Chemistry.

[21]  K. Khanna,et al.  Multiple human single-stranded DNA binding proteins function in genome maintenance: structural, biochemical and functional analysis , 2009, Critical reviews in biochemistry and molecular biology.

[22]  F. Alt,et al.  Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice , 2009, Proceedings of the National Academy of Sciences.

[23]  R. Latif,et al.  Effects of amlodipine on serum testosterone, testicular weight and gonado-somatic index in adult rats. , 2008, Journal of Ayub Medical College, Abbottabad : JAMC.

[24]  Junjie Chen,et al.  Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis , 2008, The Journal of cell biology.

[25]  Shunichi Takeda,et al.  Single-stranded DNA-binding protein hSSB1 is critical for genomic stability , 2008, Nature.

[26]  B. Gómez-González,et al.  Genome instability: a mechanistic view of its causes and consequences , 2008, Nature Reviews Genetics.

[27]  T. Helleday,et al.  DNA double-strand break repair: from mechanistic understanding to cancer treatment. , 2007, DNA repair.

[28]  I. Hickson,et al.  Molecular genetics of RecQ helicase disorders , 2007, Cellular and Molecular Life Sciences.

[29]  Y. Zou,et al.  Functions of human replication protein A (RPA): From DNA replication to DNA damage and stress responses , 2006, Journal of cellular physiology.

[30]  F. Alt,et al.  MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. , 2006, Molecular cell.

[31]  G. Kay,et al.  Melanocytes in conditional Rb-/- mice are normal in vivo but exhibit proliferation and pigmentation defects in vitro. , 2005, Pigment cell research.

[32]  S. Keeney,et al.  Surveillance of Different Recombination Defects in Mouse Spermatocytes Yields Distinct Responses despite Elimination at an Identical Developmental Stage , 2005, Molecular and Cellular Biology.

[33]  Min Wu,et al.  Development of respiratory stem cells and progenitor cells. , 2004, Stem cells and development.

[34]  F. Alt,et al.  Class-switch recombination: interplay of transcription, DNA deamination and DNA repair , 2004, Nature Reviews Immunology.

[35]  M. Dixon,et al.  Genetic background has a major effect on the penetrance and severity of craniofacial defects in mice heterozygous for the gene encoding the nucleolar protein treacle , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[36]  Judith A. Goodship,et al.  A splicing mutation affecting expression of ataxia–telangiectasia and Rad3–related protein (ATR) results in Seckel syndrome , 2003, Nature Genetics.

[37]  J. Tichelaar,et al.  SP-B deficiency causes respiratory failure in adult mice. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[38]  Michel C. Nussenzweig,et al.  Genomic Instability in Mice Lacking Histone H2AX , 2002, Science.

[39]  Philippe Soriano,et al.  Early myotome specification regulates PDGFA expression and axial skeleton development. , 2000, Development.

[40]  S. Hooper,et al.  Increased lung expansion alters the proportions of type I and type II alveolar epithelial cells in fetal sheep. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[41]  L. Adès,et al.  Severe micrognathia, cleft palate, absent olfactory tract, and abnormal rib development: cerebro-costo-mandibular syndrome or a new syndrome? , 1999, American journal of medical genetics.

[42]  K. Rajewsky,et al.  B lymphocyte-specific, Cre-mediated mutagenesis in mice. , 1997, Nucleic acids research.

[43]  Francis Collins,et al.  Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia , 1996, Cell.

[44]  A. Mccarthy.  Development , 1996, Current Opinion in Neurobiology.

[45]  K. Chrzanowska,et al.  Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. , 1995, American journal of medical genetics.

[46]  H. Colten,et al.  A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. , 1994, The Journal of clinical investigation.

[47]  H. Colten,et al.  Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. , 1993, The New England journal of medicine.

[48]  M. Rudnicki,et al.  Targeted inactivation of the muscle regulatory gene Myf-5 results in abnormal rib development and perinatal death , 1992, Cell.

[49]  R. Hennekam,et al.  The cerebro‐costo‐mandibular syndrome: third report of familial occurrence , 1985, Clinical genetics.

[50]  Martin S. Taylor,et al.  CEP152 is a genome maintenance protein disrupted in Seckel syndrome , 2011, Nature Genetics.

[51]  V. Lefebvre,et al.  Vertebrate skeletogenesis. , 2010, Current topics in developmental biology.

[52]  Yingzi Yang.  Skeletal morphogenesis during embryonic development. , 2009, Critical reviews in eukaryotic gene expression.

[53]  R. Feil,et al.  Inducible Cre mice. , 2009, Methods in molecular biology.

[54]  R. Feil.  Conditional somatic mutagenesis in the mouse using site-specific recombinases. , 2007, Handbook of experimental pharmacology.

[55]  E. M. Eddy,et al.  Male germ cell gene expression. , 2002, Recent progress in hormone research.

[56]  S. Tajbakhsh,et al.  The birth of muscle progenitor cells in the mouse: spatiotemporal considerations. , 2000, Current topics in developmental biology.

[57]  C. Iftode,et al.  Replication protein A (RPA): the eukaryotic SSB. , 1999, Critical reviews in biochemistry and molecular biology.

[58]  M. Wold.  Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. , 1997, Annual review of biochemistry.

[59]  J. Chi,et al.  Maxillo-mandibular development in cerebrocostomandibular syndrome. , 1992, Pediatric pathology.