Cell-Autonomous Progeroid Changes in Conditional Mouse Models for Repair Endonuclease XPG Deficiency

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Accumulation of DNA damage has been implicated in aging. Many premature aging syndromes are due to defective DNA repair systems. The endonuclease XPG is involved in repair of helix-distorting DNA lesions, and XPG defects cause the cancer-prone condition xeroderma pigmentosum (XP) alone or combined with the severe neurodevelopmental progeroid disorder Cockayne syndrome (CS). Here, we present a novel (conditional) Xpg−/ −⁠ mouse model which -in a C57BL6/FVB F1 hybrid background -⁠ displays many progressive progeroid features, including early cessation of growth, cachexia, kyphosis, osteoporosis, neurodegeneration, liver aging, retinal degeneration, and reduced lifespan. In a constitutive mutant with a complex phenotype it is difficult to dissect cause and consequence. We have therefore generated liver -⁠ and forebrain-specific Xpg mutants and demonstrate that they exhibit progressive anisokaryosis and neurodegeneration, respectively, indicating that a cell-intrinsic repair defect in neurons can account for neuronal degeneration. These findings strengthen the link between DNA damage and the complex process of aging.

Vyšlo v časopise: Cell-Autonomous Progeroid Changes in Conditional Mouse Models for Repair Endonuclease XPG Deficiency. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004686
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004686

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Zdroje

1. HanahanD, WeinbergRA (2011) Hallmarks of cancer: the next generation. Cell 144 : 646–674.

2. Lopez-OtinC, BlascoMA, PartridgeL, SerranoM, KroemerG (2013) The hallmarks of aging. Cell 153 : 1194–1217.

3. HoeijmakersJH (2009) DNA damage, aging, and cancer. N Engl J Med 361 : 1475–1485.

4. HoeijmakersJH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411 : 366–374.

5. FagbemiAF, OrelliB, ScharerOD (2011) Regulation of endonuclease activity in human nucleotide excision repair. DNA Repair (Amst) 10 : 722–729.

6. FriedbergEC, AguileraA, GellertM, HanawaltPC, HaysJB, et al. (2006) DNA repair: from molecular mechanism to human disease. DNA Repair (Amst) 5 : 986–996.

7. ScharerOD (2013) Nucleotide excision repair in eukaryotes. Cold Spring Harb Perspect Biol 5: a012609.

8. HanawaltPC (2008) Emerging links between premature ageing and defective DNA repair. Mech Ageing Dev 129 : 503–505.

9. NaegeliH, SugasawaK (2011) The xeroderma pigmentosum pathway: decision tree analysis of DNA quality. DNA Repair (Amst) 10 : 673–683.

10. FousteriM, MullendersLH (2008) Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects. Cell Res 18 : 73–84.

11. VermeulenW, FousteriM (2013) Mammalian transcription-coupled excision repair. Cold Spring Harb Perspect Biol 5: a012625.

12. StaresincicL, FagbemiAF, EnzlinJH, GourdinAM, WijgersN, et al. (2009) Coordination of dual incision and repair synthesis in human nucleotide excision repair. EMBO J 28 : 1111–1120.

13. EglyJM, CoinF (2011) A history of TFIIH: two decades of molecular biology on a pivotal transcription/repair factor. DNA Repair (Amst) 10 : 714–721.

14. Giglia-MariG, CoinF, RanishJA, HoogstratenD, TheilA, et al. (2004) A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A. Nat Genet 36 : 714–719.

15. ItoS, KuraokaI, ChymkowitchP, CompeE, TakedachiA, et al. (2007) XPG stabilizes TFIIH, allowing transactivation of nuclear receptors: implications for Cockayne syndrome in XP-G/CS patients. Mol Cell 26 : 231–243.

16. Le MayN, FradinD, IltisI, BougneresP, EglyJM (2012) XPG and XPF Endonucleases Trigger Chromatin Looping and DNA Demethylation for Accurate Expression of Activated Genes. Mol Cell 47 : 622–632.

17. ScharerOD (2008) XPG: its products and biological roles. Adv Exp Med Biol 637 : 83–92.

18. LakeRJ, FanHY (2013) Structure, function and regulation of CSB: a multi-talented gymnast. Mech Ageing Dev 134 : 202–211.

19. SuY, OrelliB, MadireddyA, NiedernhoferLJ, ScharerOD (2012) Multiple DNA binding domains mediate the function of the ERCC1-XPF protein in nucleotide excision repair. J Biol Chem 287 : 21846–21855.

20. Klein DouwelD, BoonenRA, LongDT, SzypowskaAA, RaschleM, et al. (2014) XPF-ERCC1 Acts in Unhooking DNA Interstrand Crosslinks in Cooperation with FANCD2 and FANCP/SLX4. Mol Cell 54 : 460–471.

21. AhmadA, RobinsonAR, DuensingA, van DrunenE, BeverlooHB, et al. (2008) ERCC1-XPF endonuclease facilitates DNA double-strand break repair. Mol Cell Biol 28 : 5082–5092.

22. D'ErricoM, ParlantiE, TesonM, de JesusBM, DeganP, et al. (2006) New functions of XPC in the protection of human skin cells from oxidative damage. EMBO J 25 : 4305–4315.

23. GorgelsTG, van der PluijmI, BrandtRM, GarinisGA, van SteegH, et al. (2007) Retinal degeneration and ionizing radiation hypersensitivity in a mouse model for Cockayne syndrome. Mol Cell Biol 27 : 1433–1441.

24. MelisJP, LuijtenM, MullendersLH, van SteegH (2011) The role of XPC: implications in cancer and oxidative DNA damage. Mutat Res 728 : 107–117.

25. TrappC, ReiteK, KlunglandA, EpeB (2007) Deficiency of the Cockayne syndrome B (CSB) gene aggravates the genomic instability caused by endogenous oxidative DNA base damage in mice. Oncogene 26 : 4044–4048.

26. MenoniH, HoeijmakersJH, VermeulenW (2012) Nucleotide excision repair-initiating proteins bind to oxidative DNA lesions in vivo. J Cell Biol 199 : 1037–1046.

27. StevnsnerT, MuftuogluM, AamannMD, BohrVA (2008) The role of Cockayne Syndrome group B (CSB) protein in base excision repair and aging. Mech Ageing Dev 129 : 441–448.

28. KlunglandA, HossM, GunzD, ConstantinouA, ClarksonSG, et al. (1999) Base excision repair of oxidative DNA damage activated by XPG protein. Mol Cell 3 : 33–42.

29. BesshoT (1999) Nucleotide excision repair 3′ endonuclease XPG stimulates the activity of base excision repair enzyme thymine glycol DNA glycosylase. Nucleic Acids Res 27 : 979–983.

30. OyamaM, WakasugiM, HamaT, HashidumeH, IwakamiY, et al. (2004) Human NTH1 physically interacts with p53 and proliferating cell nuclear antigen. Biochem Biophys Res Commun 321 : 183–191.

31. SarkerAH, TsutakawaSE, KostekS, NgC, ShinDS, et al. (2005) Recognition of RNA polymerase II and transcription bubbles by XPG, CSB, and TFIIH: insights for transcription-coupled repair and Cockayne Syndrome. Mol Cell 20 : 187–198.

32. BanerjeeD, MandalSM, DasA, HegdeML, DasS, et al. (2011) Preferential repair of oxidized base damage in the transcribed genes of mammalian cells. J Biol Chem 286 : 6006–6016.

33. ReisAM, MillsWK, RamachandranI, FriedbergEC, ThompsonD, et al. (2012) Targeted detection of in vivo endogenous DNA base damage reveals preferential base excision repair in the transcribed strand. Nucleic Acids Res 40 : 206–219.

34. GuoJ, HanawaltPC, SpivakG (2013) Comet-FISH with strand-specific probes reveals transcription-coupled repair of 8-oxoGuanine in human cells. Nucleic Acids Res 41 : 7700–7712.

35. MarteijnJA, LansH, VermeulenW, HoeijmakersJH (2014) Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol 15 : 465–481.

36. DiGiovannaJJ, KraemerKH (2012) Shining a light on xeroderma pigmentosum. J Invest Dermatol 132 : 785–796.

37. StefaniniM, BottaE, LanzafameM, OrioliD (2010) Trichothiodystrophy: from basic mechanisms to clinical implications. DNA Repair (Amst) 9 : 2–10.

38. LaugelV, DallozC, DurandM, SauvanaudF, KristensenU, et al. (2010) Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Hum Mutat 31 : 113–126.

39. KraemerKH, PatronasNJ, SchiffmannR, BrooksBP, TamuraD, et al. (2007) Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience 145 : 1388–1396.

40. AnttinenAKL, NikoskelainenE, PortinR, KurkiT, ErkinjunttiM, et al. (2008) Neurological symptoms and natural course of xeroderma pigmentosum. Brain 131 : 1979–1989.

41. NakazawaY, SasakiK, MitsutakeN, MatsuseM, ShimadaM, et al. (2012) Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair. Nat Genet 44 : 586–592.

42. SchwertmanP, LagarouA, DekkersDH, RaamsA, van der HoekAC, et al. (2012) UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair. Nat Genet 44 : 598–602.

43. ZhangX, HoribataK, SaijoM, IshigamiC, UkaiA, et al. (2012) Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair. Nat Genet 44 : 593–597.

44. FeiJ, ChenJ (2012) KIAA1530 is recruited by cockayne syndrome complementation group protein A (CSA) to participate in transcription-coupled repair (TCR). J Biol Chem 287 : 35118–35126.

45. NataleV (2011) A comprehensive description of the severity groups in Cockayne syndrome. Am J Med Genet A 155A: 1081–1095.

46. BrooksPJ (2013) Blinded by the UV light: how the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease. DNA Repair (Amst) 12 : 656–671.

47. ChoI, TsaiPF, LakeRJ, BasheerA, FanHY (2013) ATP-dependent chromatin remodeling by Cockayne syndrome protein B and NAP1-like histone chaperones is required for efficient transcription-coupled DNA repair. PLoS Genet 9: e1003407.

48. GreggSQ, RobinsonAR, NiedernhoferLJ (2011) Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease. DNA Repair (Amst) 10 : 781–791.

49. JaspersNG, RaamsA, SilengoMC, WijgersN, NiedernhoferLJ, et al. (2007) First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. Am J Hum Genet 80 : 457–466.

50. KashiyamaK, NakazawaY, PilzDT, GuoC, ShimadaM, et al. (2013) Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia. Am J Hum Genet 92 : 807–819.

51. NiedernhoferLJ, GarinisGA, RaamsA, LalaiAS, RobinsonAR, et al. (2006) A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444 : 1038–1043.

52. LehmannJ, SchubertS, SchaferA, ApelA, LaspeP, et al. (2014) An unusual mutation in the XPG gene leads to an internal in-frame deletion and a XP/CS complex phenotype. Br J Dermatol E-pub ahead of print. doi:10.1111/bjd.13035

53. ScharerOD (2008) Hot topics in DNA repair: the molecular basis for different disease states caused by mutations in TFIIH and XPG. DNA Repair (Amst) 7 : 339–344.

54. SchaferA, SchubertS, GratchevA, SeebodeC, ApelA, et al. (2013) Characterization of three XPG-defective patients identifies three missense mutations that impair repair and transcription. J Invest Dermatol 133 : 1841–1849.

55. SoltysDT, RochaCR, LernerLK, de SouzaTA, MunfordV, et al. (2013) Novel XPG (ERCC5) mutations affect DNA repair and cell survival after ultraviolet but not oxidative stress. Hum Mutat 34 : 481–489.

56. NouspikelT, LalleP, LeadonSA, CooperPK, ClarksonSG (1997) A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: implications for a second XPG function. Proc Natl Acad Sci U S A 94 : 3116–3121.

57. EmmertS, SlorH, BuschDB, BatkoS, AlbertRB, et al. (2002) Relationship of neurologic degeneration to genotype in three xeroderma pigmentosum group G patients. J Invest Dermatol 118 : 972–982.

58. SchaferA, GratchevA, SeebodeC, HofmannL, SchubertS, et al. (2013) Functional and molecular genetic analyses of nine newly identified XPD-deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex phenotypes. Exp Dermatol 22 : 486–489.

59. FriedbergEC, MeiraLB (2006) Database of mouse strains carrying targeted mutations in genes affecting biological responses to DNA damage Version 7. DNA Repair (Amst) 5 : 189–209.

60. WijnhovenSW, HoogervorstEM, de WaardH, van der HorstGT, van SteegH (2007) Tissue specific mutagenic and carcinogenic responses in NER defective mouse models. Mutat Res 614 : 77–94.

61. NiedernhoferLJ (2008) Nucleotide excision repair deficient mouse models and neurological disease. DNA Repair (Amst) 7 : 1180–1189.

62. JaarsmaD, van der PluijmI, van der HorstGT, HoeijmakersJH (2013) Cockayne syndrome pathogenesis: Lessons from mouse models. Mech Ageing Dev 134 : 180–195.

63. HaradaYN, ShiomiN, KoikeM, IkawaM, OkabeM, et al. (1999) Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene. Mol Cell Biol 19 : 2366–2372.

64. TianM, JonesDA, SmithM, ShinkuraR, AltFW (2004) Deficiency in the Nuclease Activity of Xeroderma Pigmentosum G in Mice Leads to Hypersensitivity to UV Irradiation. Mol Cell Biol 24 : 2237–2242.

65. ShiomiN, KitoS, OyamaM, MatsunagaT, HaradaYN, et al. (2004) Identification of the XPG Region That Causes the Onset of Cockayne Syndrome by Using Xpg Mutant Mice Generated by the cDNA-Mediated Knock-In Method. Mol Cell Biol 24 : 3712–3719.

66. ShiomiN, MoriM, KitoS, HaradaYN, TanakaK, et al. (2005) Severe growth retardation and short life span of double-mutant mice lacking Xpa and exon 15 of Xpg. DNA Repair (Amst) 4 : 351–357.

67. LaposaRR, HuangEJ, CleaverJE (2007) Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice. Proc Natl Acad Sci U S A 104 : 1389–1394.

68. van der PluijmI, GarinisGA, BrandtRM, GorgelsTG, WijnhovenSW, et al. (2007) Impaired genome maintenance suppresses the growth hormone–insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biol 5: e2.

69. MuraiM, EnokidoY, InamuraN, YoshinoM, NakatsuY, et al. (2001) Early postnatal ataxia and abnormal cerebellar development in mice lacking Xeroderma pigmentosum Group A and Cockayne syndrome Group B DNA repair genes. Proc Natl Acad Sci U S A 98 : 13379–13384.

70. AndressooJO, WeedaG, de WitJ, MitchellJR, BeemsRB, et al. (2009) An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair. Mol Cell Biol 29 : 1276–1290.

71. AndressooJO, MitchellJR, de WitJ, HoogstratenD, VolkerM, et al. (2006) An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria. Cancer Cell 10 : 121–132.

72. WeedaG, DonkerI, de WitJ, MorreauH, JanssensR, et al. (1997) Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence. Curr Biol 7 : 427–439.

73. SakaiK, MiyazakiJ (1997) A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. Biochem Biophys Res Commun 237 : 318–324.

74. NakaneH, TakeuchiS, YubaS, SaijoM, NakatsuY, et al. (1995) High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene. Nature 377 : 165–168.

75. JaspersNG, RaamsA, KelnerMJ, NgJM, YamashitaYM, et al. (2002) Anti-tumour compounds illudin S and Irofulven induce DNA lesions ignored by global repair and exclusively processed by transcription -⁠ and replication-coupled repair pathways. DNA Repair (Amst) 1 : 1027–1038.

76. VoN, SeoHY, RobinsonA, SowaG, BentleyD, et al. (2010) Accelerated aging of intervertebral discs in a mouse model of progeria. J Orthop Res 28 : 1600–1607.

77. de BoerJ, AndressooJO, de WitJ, HuijmansJ, BeemsRB, et al. (2002) Premature aging in mice deficient in DNA repair and transcription. Science 296 : 1276–1279.

78. NicolaijeC, DiderichKE, BotterSM, PriemelM, WaarsingJH, et al. (2012) Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice. PLoS ONE 7: e35246.

79. DiderichKE, NicolaijeC, PriemelM, WaarsingJH, DayJS, et al. (2012) Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice. Age (Dordr) 34 : 845–861.

80. TianM, ShinkuraR, ShinkuraN, AltFW (2004) Growth Retardation, Early Death, and DNA Repair Defects in Mice Deficient for the Nucleotide Excision Repair Enzyme XPF. Mol Cell Biol 24 : 1200–1205.

81. McWhirJ, SelfridgeJ, HarrisonDJ, SquiresS, MeltonDW (1993) Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning. Nat Genet 5 : 217–224.

82. GreggSQ, GutierrezV, RobinsonAR, WoodellT, NakaoA, et al. (2012) A mouse model of accelerated liver aging caused by a defect in DNA repair. Hepatology 55 : 609–621.

83. SelfridgeJ, HsiaKT, RedheadNJ, MeltonDW (2001) Correction of liver dysfunction in DNA repair-deficient mice with an ERCC1 transgene. Nucleic Acids Res 29 : 4541–4550.

84. GarinisGA, UittenboogaardLM, StachelscheidH, FousteriM, van IjckenW, et al. (2009) Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity. Nat Cell Biol 11 : 604–615.

85. van de VenM, AndressooJO, HolcombVB, von LindernM, JongWM, et al. (2006) Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice. PLoS Genet 2: e192.

86. KenslerTW, WakabayashiN, BiswalS (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47 : 89–116.

87. el-DeiryWS (1998) Regulation of p53 downstream genes. Semin Cancer Biol 8 : 345–357.

88. ChipchaseMD, O'NeillM, MeltonDW (2003) Characterization of premature liver polyploidy in DNA repair (Ercc1)-deficient mice. Hepatology 38 : 958–966.

89. BorgesiusNZ, de WaardMC, van der PluijmI, OmraniA, ZondagGC, et al. (2011) Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair. J Neurosci 31 : 12543–12553.

90. de WaardMC, van der PluijmI, Zuiderveen BorgesiusN, ComleyLH, HaasdijkED, et al. (2010) Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice. Acta Neuropathol 120 : 461–475.

91. JaarsmaD, van der PluijmI, de WaardMC, HaasdijkED, BrandtR, et al. (2011) Age-related neuronal degeneration: complementary roles of nucleotide excision repair and transcription-coupled repair in preventing neuropathology. PLoS Genet 7: e1002405.

92. de GraafEL, VermeijWP, de WaardMC, RijksenY, van der PluijmI, et al. (2013) Spatio-temporal analysis of molecular determinants of neuronal degeneration in the aging mouse cerebellum. Mol Cell Proteomics 12 : 1350–1362.

93. AdalbertR, ColemanMP (2013) Review: Axon pathology in age-related neurodegenerative disorders. Neuropathol Appl Neurobiol 39 : 90–108.

94. WeidenheimKM, DicksonDW, RapinI (2009) Neuropathology of Cockayne syndrome: Evidence for impaired development, premature aging, and neurodegeneration. Mech Ageing Dev 130 : 619–636.

95. PosticC, ShiotaM, NiswenderKD, JettonTL, ChenY, et al. (1999) Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem 274 : 305–315.

96. Beyer TAXW, TeupserD, auf dem KellerU, BugnonP, HildtE, et al. (2008) Impaired liver regeneration in Nrf2 knockout mice: role of ROS-mediated insulin/IGF-1 resistance. EMBO J 9 : 212–223.

97. ItohM, HayashiM, ShiodaK, MinagawaM, IsaF, et al. (1999) Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev 21 : 326–333.

98. KoobM, LaugelV, DurandM, FothergillH, DallozC, et al. (2010) Neuroimaging in Cockayne syndrome. AJNR Am J Neuroradiol 31 : 1623–1630.

99. HayashiM, Miwa-SaitoN, TanumaN, KubotaM (2012) Brain vascular changes in Cockayne syndrome. Neuropathology 32 : 113–117.

100. IwasatoT, NomuraR, AndoR, IkedaT, TanakaM, et al. (2004) Dorsal telencephalon-specific expression of Cre recombinase in PAC transgenic mice. Genesis 38 : 130–138.

101. LemonRN, JohanssonRS, WestlingG (1995) Corticospinal control during reach, grasp, and precision lift in man. J Neurosci 15 : 6145–6156.

102. RotshenkerS (2009) The role of Galectin-3/MAC-2 in the activation of the innate-immune function of phagocytosis in microglia in injury and disease. J Mol Neurosci 39 : 99–103.

103. LeeSK, YuSL, PrakashL, PrakashS (2002) Requirement of yeast RAD2, a homolog of human XPG gene, for efficient RNA polymerase II transcription. implications for Cockayne syndrome. Cell 109 : 823–834.

104. ThorelF, ConstantinouA, Dunand-SauthierI, NouspikelT, LalleP, et al. (2004) Definition of a short region of XPG necessary for TFIIH interaction and stable recruitment to sites of UV damage. Mol Cell Biol 24 : 10670–10680.

105. TregoKS, ChernikovaSB, DavalosAR, PerryJJ, FingerLD, et al. (2011) The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome. Cell Cycle 10 : 1998–2007.

106. BraceLE, VoseSC, VargasDF, ZhaoS, WangXP, et al. (2013) Lifespan extension by dietary intervention in a mouse model of Cockayne syndrome uncouples early postnatal development from segmental progeria. Aging Cell 12 : 1144–1147.

107. AndressooJO, JansJ, de WitJ, CoinF, HoogstratenD, et al. (2006) Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles. PLoS Biol 4: e322.

108. VermeulenW, JaekenJ, JaspersNG, BootsmaD, HoeijmakersJH (1993) Xeroderma pigmentosum complementation group G associated with Cockayne syndrome. Am J Hum Genet 53 : 185–192.

109. SchumacherB, van der PluijmI, MoorhouseMJ, KosteasT, RobinsonAR, et al. (2008) Delayed and accelerated aging share common longevity assurance mechanisms. PLoS Genet 4: e1000161.

110. VermeijWP, HoeijmakersJHJ, PothofJ (2014) Aging: Not All DNA Damage is Equal. Curr Opin Genet Dev In press.

111. SunXZ, HaradaYN, TakahashiS, ShiomiN, ShiomiT (2001) Purkinje cell degeneration in mice lacking the xeroderma pigmentosum group G gene. J Neurosci Res 64 : 348–354.

112. VeghMJ, de WaardMC, van der PluijmI, RidwanY, SassenMJ, et al. (2012) Synaptic proteome changes in a DNA repair deficient ercc1 mouse model of accelerated aging. J Proteome Res 11 : 1855–1867.

113. MelisJP, WijnhovenSW, BeemsRB, RoodbergenM, van den BergJ, et al. (2008) Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes. Cancer Res 68 : 1347–1353.

114. LeeYJ, ParkSJ, CicconeSL, KimCR, LeeSH (2006) An in vivo analysis of MMC-induced DNA damage and its repair. Carcinogenesis 27 : 446–453.

115. D'ErricoM, ParlantiE, TesonM, DeganP, LemmaT, et al. (2007) The role of CSA in the response to oxidative DNA damage in human cells. Oncogene 26 : 4336–4343.

116. SpivakG, HanawaltPC (2006) Host cell reactivation of plasmids containing oxidative DNA lesions is defective in Cockayne syndrome but normal in UV-sensitive syndrome fibroblasts. DNA Repair (Amst) 5 : 13–22.

117. de WaardH, de WitJ, GorgelsTG, van den AardwegG, AndressooJO, et al. (2003) Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice. DNA Repair (Amst) 2 : 13–25.

118. de WaardH, de WitJ, AndressooJO, van OostromCT, RiisB, et al. (2004) Different effects of CSA and CSB deficiency on sensitivity to oxidative DNA damage. Mol Cell Biol 24 : 7941–7948.

119. HalliwellB (2003) Oxidative stress in cell culture: an under-appreciated problem? FEBS Letters 540 : 3–6.

120. TotonchyMB, TamuraD, PantellMS, ZalewskiC, BradfordPT, et al. (2013) Auditory analysis of xeroderma pigmentosum 1971–2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration. Brain 136 : 194–208.

121. SchaftJ, Ashery-PadanR, van der HoevenF, GrussP, StewartAF (2001) Efficient FLP recombination in mouse ES cells and oocytes. Genesis 31 : 6–10.

122. WaarsingJH, DayJS, WeinansH (2004) An improved segmentation method for in vivo microCT imaging. J Bone Miner Res 19 : 1640–1650.

123. BotterSM, GlassonSS, HopkinsB, ClockaertsS, WeinansH, et al. (2009) ADAMTS5−/ −⁠ mice have less subchondral bone changes after induction of osteoarthritis through surgical instability: implications for a link between cartilage and subchondral bone changes. Osteoarthritis Cartilage 17 : 636–645.

124. PfafflMW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29: e45.