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


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.


Vyšlo v časopise: Essential Developmental, Genomic Stability, and Tumour Suppressor Functions of the Mouse Orthologue of. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003298
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1003298

Souhrn

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.


Zdroje

1. BhattiS, KozlovS, FarooqiAA, NaqiA, LavinM, et al. (2011) ATM protein kinase: the linchpin of cellular defenses to stress. Cell Mol Life Sci 68: 2977–3006.

2. HelledayT, LoJ, van GentDC, EngelwardBP (2007) DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair (Amst) 6: 923–935.

3. RichardDJ, BoldersonE, KhannaKK (2009) Multiple human single-stranded DNA binding proteins function in genome maintenance: structural, biochemical and functional analysis. Crit Rev Biochem Mol Biol 44: 98–116.

4. IftodeC, DanielyY, BorowiecJA (1999) Replication protein A (RPA): the eukaryotic SSB. Crit Rev Biochem Mol Biol 34: 141–180.

5. WoldMS (1997) Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu Rev Biochem 66: 61–92.

6. ZouY, LiuY, WuX, ShellSM (2006) Functions of human replication protein A (RPA): from DNA replication to DNA damage and stress responses. J Cell Physiol 208: 267–273.

7. RichardDJ, BoldersonE, CubedduL, WadsworthRI, SavageK, et al. (2008) Single-stranded DNA-binding protein hSSB1 is critical for genomic stability. Nature 453: 677–681.

8. HuangJ, GongZ, GhosalG, ChenJ (2009) SOSS complexes participate in the maintenance of genomic stability. Mol Cell 35: 384–393.

9. LiY, BoldersonE, KumarR, MuniandyPA, XueY, et al. (2009) HSSB1 and hSSB2 form similar multiprotein complexes that participate in DNA damage response. J Biol Chem 284: 23525–23531.

10. SkaarJR, RichardDJ, SarafA, ToschiA, BoldersonE, et al. (2009) INTS3 controls the hSSB1-mediated DNA damage response. J Cell Biol 187: 25–32.

11. ZhangF, WuJ, YuX (2009) Integrator3, a partner of single-stranded DNA-binding protein 1, participates in the DNA damage response. J Biol Chem 284: 30408–30415.

12. NogeeLM, de MelloDE, DehnerLP, ColtenHR (1993) Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med 328: 406–410.

13. NogeeLM, GarnierG, DietzHC, SingerL, MurphyAM, et al. (1994) A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest 93: 1860–1863.

14. MeltonKR, NessleinLL, IkegamiM, TichelaarJW, ClarkJC, et al. (2003) SP-B deficiency causes respiratory failure in adult mice. Am J Physiol Lung Cell Mol Physiol 285: L543–549.

15. FlecknoeS, HardingR, MaritzG, HooperSB (2000) Increased lung expansion alters the proportions of type I and type II alveolar epithelial cells in fetal sheep. Am J Physiol Lung Cell Mol Physiol 278: L1180–1185.

16. WuM, WeiYQ (2004) Development of respiratory stem cells and progenitor cells. Stem Cells Dev 13: 607–613.

17. ChaudhuriJ, AltFW (2004) Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat Rev Immunol 4: 541–552.

18. FeilR (2007) Conditional somatic mutagenesis in the mouse using site-specific recombinases. Handb Exp Pharmacol 3–28.

19. BarlowC, HirotsuneS, PaylorR, LiyanageM, EckhausM, et al. (1996) Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86: 159–171.

20. CelesteA, PetersenS, RomanienkoPJ, Fernandez-CapetilloO, ChenHT, et al. (2002) Genomic instability in mice lacking histone H2AX. Science 296: 922–927.

21. LouZ, Minter-DykhouseK, FrancoS, GostissaM, RiveraMA, et al. (2006) MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol Cell 21: 187–200.

22. LiangY, GaoH, LinSY, PengG, HuangX, et al. (2010) BRIT1/MCPH1 is essential for mitotic and meiotic recombination DNA repair and maintaining genomic stability in mice. PLoS Genet 6: e1000826 doi:10.1371/journal.pgen.1000826.

23. LatifR, LodhiGM, AslamM (2008) Effects of amlodipine on serum testosterone, testicular weight and gonado-somatic index in adult rats. J Ayub Med Coll Abbottabad 20: 8–10.

24. BarchiM, MahadevaiahS, Di GiacomoM, BaudatF, de RooijDG, et al. (2005) Surveillance of different recombination defects in mouse spermatocytes yields distinct responses despite elimination at an identical developmental stage. Mol Cell Biol 25: 7203–7215.

25. HanadaK, HicksonID (2007) Molecular genetics of RecQ helicase disorders. Cell Mol Life Sci 64: 2306–2322.

26. KalayE, YigitG, AslanY, BrownKE, PohlE, et al. (2011) CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet 43: 23–26.

27. O'DriscollM, Ruiz-PerezVL, WoodsCG, JeggoPA, GoodshipJA (2003) A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33: 497–501.

28. FarooqM, BaigS, TommerupN, KjaerKW (2010) 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. Am J Med Genet A 152A: 495–497.

29. QvistP, HuertasP, JimenoS, NyegaardM, HassanMJ, et al. (2011) CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet 7: e1002310 doi:10.1371/journal.pgen.1002310.

30. ChrzanowskaKH, KleijerWJ, Krajewska-WalasekM, BialeckaM, GutkowskaA, et al. (1995) Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. Am J Med Genet 57: 462–471.

31. RichardDJ, CubedduL, UrquhartAJ, BainA, BoldersonE, et al. (2011) hSSB1 interacts directly with the MRN complex stimulating its recruitment to DNA double-strand breaks and its endo-nuclease activity. Nucleic Acids Res 39: 3643–3651.

32. LefebvreV, BhattaramP (2010) Vertebrate skeletogenesis. Curr Top Dev Biol 90: 291–317.

33. YangY (2009) Skeletal morphogenesis during embryonic development. Crit Rev Eukaryot Gene Expr 19: 197–218.

34. MarotoM, BoneRA, DaleJK (2012) Somitogenesis. Development 139: 2453–2456.

35. TajbakhshS, BuckinghamM (2000) The birth of muscle progenitor cells in the mouse: spatiotemporal considerations. Curr Top Dev Biol 48: 225–268.

36. BraunT, RudnickiMA, ArnoldHH, JaenischR (1992) Targeted inactivation of the muscle regulatory gene Myf-5 results in abnormal rib development and perinatal death. Cell 71: 369–382.

37. TallquistMD, WeismannKE, HellstromM, SorianoP (2000) Early myotome specification regulates PDGFA expression and axial skeleton development. Development 127: 5059–5070.

38. HennekamRC, BeemerFA, HuijbersWA, HustinxPA, van SprangFJ (1985) The cerebro-costo-mandibular syndrome: third report of familial occurrence. Clin Genet 28: 118–121.

39. KirkEP, ArbuckleS, RammPL, AdesLC (1999) Severe micrognathia, cleft palate, absent olfactory tract, and abnormal rib development: cerebro-costo-mandibular syndrome or a new syndrome? Am J Med Genet 84: 120–124.

40. KangYK, LeeSK, ChiJG (1992) Maxillo-mandibular development in cerebrocostomandibular syndrome. Pediatr Pathol 12: 717–724.

41. Franz-OdendaalTA (2011) Induction and patterning of intramembranous bone. Front Biosci 16: 2734–2746.

42. MackieEJ, TatarczuchL, MiramsM (2011) The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification. J Endocrinol 211: 109–121.

43. FeldhahnN, FerrettiE, RobbianiDF, CallenE, DeroubaixS, et al. (2012) The hSSB1 orthologue Obfc2b is essential for skeletogenesis but dispensable for the DNA damage response in vivo. EMBO J

44. DixonJ, DixonMJ (2004) 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. Dev Dyn 229: 907–914.

45. EddyEM (2002) Male germ cell gene expression. Recent Prog Horm Res 57: 103–128.

46. AguileraA, Gomez-GonzalezB (2008) Genome instability: a mechanistic view of its causes and consequences. Nat Rev Genet 9: 204–217.

47. Minter-DykhouseK, WardI, HuenMS, ChenJ, LouZ (2008) Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis. J Cell Biol 181: 727–735.

48. KimHS, VassilopoulosA, WangRH, LahusenT, XiaoZ, et al. (2011) SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 20: 487–499.

49. LiL, HalabyMJ, HakemA, CardosoR, El GhamrasniS, et al. (2010) Rnf8 deficiency impairs class switch recombination, spermatogenesis, and genomic integrity and predisposes for cancer. J Exp Med 207: 983–997.

50. MoynahanME, JasinM (2010) Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 11: 196–207.

51. TonksID, HackerE, IrwinN, MullerHK, KeithP, et al. (2005) Melanocytes in conditional Rb−/− mice are normal in vivo but exhibit proliferation and pigmentation defects in vitro. Pigment Cell Res 18: 252–264.

52. FeilS, ValtchevaN, FeilR (2009) Inducible Cre mice. Methods Mol Biol 530: 343–363.

53. RickertRC, RoesJ, RajewskyK (1997) B lymphocyte-specific, Cre-mediated mutagenesis in mice. Nucleic Acids Res 25: 1317–1318.

54. BruceSJ, ButterfieldNC, MetzisV, TownL, McGlinnE, et al. (2010) Inactivation of Patched1 in the mouse limb has novel inhibitory effects on the chondrogenic program. J Biol Chem 285: 27967–27981.

55. BirdAD, FlecknoeSJ, TanKH, OlssonPF, AntonyN, et al. (2011) cAMP response element binding protein is required for differentiation of respiratory epithelium during murine development. PLoS ONE 6: e17843 doi:10.1371/journal.pone.0017843.

56. O'BrienKB, Alberich-JordaM, YadavN, KocherO, DiruscioA, et al. (2010) CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells. Development 137: 2147–2156.

57. JuradoS, SmythI, van DenderenB, TenisN, HammetA, et al. (2010) Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis. PLoS Genet 6: e1001170 doi:10.1371/journal.pgen.1001170.

58. ChengHL, VuongBQ, BasuU, FranklinA, SchwerB, et al. (2009) Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice. Proc Natl Acad Sci U S A 106: 2717–2722.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2013 Číslo 2
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa