Hypersensitivity of Primordial Germ Cells to Compromised Replication-Associated DNA Repair Involves ATM-p53-p21 Signaling

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The precursors to sperm and eggs begin are a group of <100 cells in the embryo, called primordial germ cells (PGCs). They migrate in the primitive embryo to the location of the future gonads, then undergo a rapid proliferation over the next few days to a population of many thousands. Because these cells contain the precious genetic information for our offspring, and the DNA replication associated with rapid PGC proliferation is subject to spontaneous errors, mechanisms exist to avoid propagation of mutations. A manifestation of this is the high sensitivity of PGCs to genetic perturbations affecting DNA repair. We studied mice defective for a gene called Fanconi anemia M (Fancm) that is important for repair of DNA damage that occurs during replication. Although it is expressed in all tissues, only the PGCs are affected in mutants, and are reduced in number. We find that PGCs lacking Fancm respond by slowing cell division, and identified the genetic pathway responsible for this protective response.

Vyšlo v časopise: Hypersensitivity of Primordial Germ Cells to Compromised Replication-Associated DNA Repair Involves ATM-p53-p21 Signaling. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004471
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004471

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1. KimH, D'AndreaAD (2012) Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev 26: 1393–1408.

2. KottemannMC, SmogorzewskaA (2013) Fanconi anaemia and the repair of Watson and Crick DNA crosslinks. Nature 493: 356–363.

3. BoglioloM, SchusterB, StoepkerC, DerkuntB, SuY, et al. (2013) Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet 92: 800–806.

4. 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.

5. KnipscheerP, RaschleM, SmogorzewskaA, EnoiuM, HoTV, et al. (2009) The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science 326: 1698–1701.

6. Garcia-HigueraI, TaniguchiT, GanesanS, MeynMS, TimmersC, et al. (2001) Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell 7: 249–262.

7. SinghTR, BakkerST, AgarwalS, JansenM, GrassmanE, et al. (2009) Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M. Blood 114: 174–180.

8. KimJM, KeeY, GurtanA, D'AndreaAD (2008) Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24. Blood 111: 5215–5222.

9. AndreassenPR, D'AndreaAD, TaniguchiT (2004) ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev 18: 1958–1963.

10. WangX, AndreassenPR, D'AndreaAD (2004) Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol 24: 5850–5862.

11. WangY, LeungJW, JiangY, LoweryMG, DoH, et al. (2013) FANCM and FAAP24 maintain genome stability via cooperative as well as unique functions. Mol Cell 49: 997–1009.

12. GariK, DecailletC, StasiakAZ, StasiakA, ConstantinouA (2008) The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks. Mol Cell 29: 141–148.

13. AlterBP, FrissoraCL, HalperinDS, FreedmanMH, ChitkaraU, et al. (1991) Fanconi's anaemia and pregnancy. Br J Haematol 77: 410–418.

14. AuerbachAD (2009) Fanconi anemia and its diagnosis. Mutat Res 668: 4–10.

15. AgoulnikAI, LuB, ZhuQ, TruongC, TyMT, et al. (2002) A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd. Hum Mol Genet 11: 3047–3053.

16. BakkerST, van de VrugtHJ, VisserJA, Delzenne-GoetteE, van der WalA, et al. (2012) Fancf-deficient mice are prone to develop ovarian tumours. J Pathol 226: 28–39.

17. ParmarK, D'AndreaA, NiedernhoferLJ (2009) Mouse models of Fanconi anemia. Mutat Res 668: 133–140.

18. BakkerST, van de VrugtHJ, RooimansMA, OostraAB, SteltenpoolJ, et al. (2009) Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M. Hum Mol Genet 18: 3484–3495.

19. CrossanGP, van der WeydenL, RosadoIV, LangevinF, GaillardPH, et al. (2011) Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nat Genet 43: 147–152.

20. WhitneyMA, RoyleG, LowMJ, KellyMA, AxthelmMK, et al. (1996) Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconi anemia C gene. Blood 88: 49–58.

21. WongJC, AlonN, McKerlieC, HuangJR, MeynMS, et al. (2003) Targeted disruption of exons 1 to 6 of the Fanconi Anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia. Hum Mol Genet 12: 2063–2076.

22. HoughtalingS, TimmersC, NollM, FinegoldMJ, JonesSN, et al. (2003) Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice. Genes Dev 17: 2021–2035.

23. NadlerJJ, BraunRE (2000) Fanconi anemia complementation group C is required for proliferation of murine primordial germ cells. Genesis 27: 117–123.

24. ConradDF, KeeblerJE, DePristoMA, LindsaySJ, ZhangY, et al. (2011) Variation in genome-wide mutation rates within and between human families. Nat Genet 43: 712–714.

25. SimpsonAJ (1997) The natural somatic mutation frequency and human carcinogenesis. Adv Cancer Res 71: 209–240.

26. GartnerA, MilsteinS, AhmedS, HodgkinJ, HengartnerMO (2000) A conserved checkpoint pathway mediates DNA damage–induced apoptosis and cell cycle arrest in C. elegans. Mol Cell 5: 435–443.

27. ShimaN, HartfordSA, DuffyT, WilsonLA, SchimentiKJ, et al. (2003) Phenotype-based identification of mouse chromosome instability mutants. Genetics 163: 1031–1040.

28. MoranJL, BoltonAD, TranPV, BrownA, DwyerND, et al. (2006) Utilization of a whole genome SNP panel for efficient genetic mapping in the mouse. Genome Res 16: 436–440.

29. SchimentiJ (2005) Synapsis or silence. Nat Genet 37: 11–13.

30. Durcova-HillsG, CapelB (2008) Development of germ cells in the mouse. Curr Top Dev Biol 83: 185–212.

31. TamPP, SnowMH (1981) Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. J Embryol Exp Morphol 64: 133–147.

32. KimB, KimY, SakumaR, HuiCC, RutherU, et al. (2011) Primordial germ cell proliferation is impaired in Fused Toes mutant embryos. Dev Biol 349: 417–426.

33. WagaS, LiR, StillmanB (1997) p53-induced p21 controls DNA replication. Leukemia 11 Suppl 3: 321–323.

34. el-DeiryWS, TokinoT, VelculescuVE, LevyDB, ParsonsR, et al. (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825.

35. HarperJW, AdamiGR, WeiN, KeyomarsiK, ElledgeSJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805–816.

36. XiongY, HannonGJ, ZhangH, CassoD, KobayashiR, et al. (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704.

37. SirbuBM, CortezD (2013) DNA damage response: three levels of DNA repair regulation. Cold Spring Harb Perspect Biol 5: a012724.

38. LevittPS, ZhuM, CassanoA, YazinskiSA, LiuH, et al. (2007) Genome maintenance defects in cultured cells and mice following partial inactivation of the essential cell cycle checkpoint gene Hus1. Mol Cell Biol 27: 2189–2201.

39. HiraoA, CheungA, DuncanG, GirardPM, EliaAJ, et al. (2002) Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Mol Cell Biol 22: 6521–6532.

40. Bolcun-FilasE, RinaldiVD, WhiteME, SchimentiJC (2014) Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science 343: 533–536.

41. TaoY, JinC, LiX, QiS, ChuL, et al. (2012) The structure of the FANCM-MHF complex reveals physical features for functional assembly. Nat Commun 3: 782.

42. HuangM, KennedyR, AliAM, MoreauLA, MeeteiAR, et al. (2011) Human MutS and FANCM complexes function as redundant DNA damage sensors in the Fanconi Anemia pathway. DNA Repair (Amst) 10: 1203–1212.

43. MosedaleG, NiedzwiedzW, AlpiA, PerrinaF, Pereira-LealJB, et al. (2005) The vertebrate Hef ortholog is a component of the Fanconi anemia tumor-suppressor pathway. Nat Struct Mol Biol 12: 763–771.

44. MeeteiAR, MedhurstAL, LingC, XueY, SinghTR, et al. (2005) A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet 37: 958–963.

45. CrismaniW, GirardC, FrogerN, PradilloM, SantosJL, et al. (2012) FANCM limits meiotic crossovers. Science 336: 1588–1590.

46. KnollA, HigginsJD, SeeligerK, RehaSJ, DangelNJ, et al. (2012) The Fanconi anemia ortholog FANCM ensures ordered homologous recombination in both somatic and meiotic cells in Arabidopsis. Plant Cell 24: 1448–1464.

47. LorenzA, OsmanF, SunW, NandiS, SteinacherR, et al. (2012) The fission yeast FANCM ortholog directs non-crossover recombination during meiosis. Science 336: 1585–1588.

48. HuangJ, LiuS, BellaniMA, ThazhathveetilAK, LingC, et al. (2013) The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks. Mol Cell 52: 434–446.

49. MeeteiAR, MedhurstAL, LingC, XueY, SinghTR, et al. (2005) A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nature genetics 37: 958–963.

50. BlackfordAN, SchwabRA, NieminuszczyJ, DeansAJ, WestSC, et al. (2012) The DNA translocase activity of FANCM protects stalled replication forks. Human molecular genetics 21: 2005–2016.

51. SobeckA, StoneS, LandaisI, de GraafB, HoatlinME (2009) The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways. J Biol Chem 284: 25560–25568.

52. KennedyRD, ChenCC, StuckertP, ArchilaEM, De la VegaMA, et al. (2007) Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. J Clin Invest 117: 1440–1449.

53. JenkinsC, KanJ, HoatlinME (2012) Targeting the fanconi anemia pathway to identify tailored anticancer therapeutics. Anemia 2012: 481583.

54. LandaisI, HiddinghS, McCarrollM, YangC, SunA, et al. (2009) Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors. Mol Cancer 8: 133.

55. VousdenKH, PrivesC (2009) Blinded by the Light: The Growing Complexity of p53. Cell 137: 413–431.

56. BouwmanP, DrostR, KlijnC, PieterseM, van der GuldenH, et al. (2011) Loss of p53 partially rescues embryonic development of Palb2 knockout mice but does not foster haploinsufficiency of Palb2 in tumour suppression. J Pathol 224: 10–21.

57. KuznetsovS, PellegriniM, ShudaK, Fernandez-CapetilloO, LiuY, et al. (2007) RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. J Cell Biol 176: 581–592.

58. CeccaldiR, ParmarK, MoulyE, DelordM, KimJM, et al. (2012) Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell 11: 36–49.

59. Rodriguez-MariA, CanestroC, BremillerRA, Nguyen-JohnsonA, AsakawaK, et al. (2010) Sex reversal in zebrafish fancl mutants is caused by Tp53-mediated germ cell apoptosis. PLoS Genet 6: e1001034.

60. Di GiacomoM, BarchiM, BaudatF, EdelmannW, KeeneyS, et al. (2005) Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. PNAS 102: 737–742.

61. AdelmanCA, LoloRL, BirkbakNJ, MurinaO, MatsuzakiK, et al. (2013) HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis. Nature 502: 381–384.

62. LuebbenSW, KawabataT, AkreMK, LeeWL, JohnsonCS, et al. (2013) Helq acts in parallel to Fancc to suppress replication-associated genome instability. Nucleic Acids Res 41: 10283–10297.

63. HartfordSA, LuoY, SouthardTL, MinIM, LisJT, et al. (2011) Minichromosome maintenance helicase paralog MCM9 is dispensible for DNA replication but functions in germ-line stem cells and tumor suppression. Proc Natl Acad Sci U S A 108: 17702–17707.

64. AtchisonFW, CapelB, MeansAR (2003) Pin1 regulates the timing of mammalian primordial germ cell proliferation. Development 130: 3579–3586.

65. WatanabeN, MiiS, AsaiN, AsaiM, NiimiK, et al. (2013) The REV7 subunit of DNA polymerase zeta is essential for primordial germ cell maintenance in the mouse. J Biol Chem 288: 10459–10471.

66. KhalajM, AbbasiA, YamanishiH, AkiyamaK, WakitaniS, et al. (2014) A Missense Mutation in Rev7 Disrupts Formation of Polzeta, Impairing Mouse Development and Repair of Genotoxic Agent-induced DNA Lesions. J Biol Chem 289: 3811–3824.

67. TakataK, RehS, TomidaJ, PersonMD, WoodRD (2013) Human DNA helicase HELQ participates in DNA interstrand crosslink tolerance with ATR and RAD51 paralogs. Nat Commun 4: 2338.

68. ParkJ, LongDT, LeeKY, AbbasT, ShibataE, et al. (2013) The MCM8-MCM9 complex promotes RAD51 recruitment at DNA damage sites to facilitate homologous recombination. Mol Cell Biol 33: 1632–1644.

69. LutzmannM, GreyC, TraverS, GanierO, Maya-MendozaA, et al. (2012) MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination. Mol Cell 47: 523–534.

70. NishimuraK, IshiaiM, HorikawaK, FukagawaT, TakataM, et al. (2012) Mcm8 and Mcm9 form a complex that functions in homologous recombination repair induced by DNA interstrand crosslinks. Mol Cell 47: 511–522.

71. RoyoH, PolikiewiczG, MahadevaiahSK, ProsserH, MitchellM, et al. (2010) Evidence that meiotic sex chromosome inactivation is essential for male fertility. Current Biol 20: 2117–2123.

72. WesolyJ, AgarwalS, SigurdssonS, BussenW, Van KomenS, et al. (2006) Differential contributions of mammalian Rad54 paralogs to recombination, DNA damage repair, and meiosis. Mol Cell Biol 26: 976–989.

73. RayaA, Rodriguez-PizaI, GuenecheaG, VassenaR, NavarroS, et al. (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460: 53–59.

74. MullerLUW, MilsomMD, HarrisCE, VyasR, BrummeKM, et al. (2012) Overcoming reprogramming resistance of Fanconi anemia cells. Blood 119: 5449–5457.

75. ReinholdtL, AshleyT, SchimentiJ, ShimaN (2004) Forward genetic screens for meiotic and mitotic recombination-defective mutants in mice. Methods Mol Biol 262: 87–107.

76. StrykeD, KawamotoM, HuangCC, JohnsSJ, KingLA, et al. (2003) BayGenomics: a resource of insertional mutations in mouse embryonic stem cells. Nucleic Acids Res 31: 278–281.

77. LevittPS, LiuH, ManningC, WeissRS (2005) Conditional inactivation of the mouse Hus1 cell cycle checkpoint gene. Genomics 86: 212–224.

78. BrugarolasJ, ChandrasekaranC, GordonJI, BeachD, JacksT, et al. (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377: 552–557.

79. JacksT, RemingtonL, WilliamsBO, SchmittEM, HalachmiS, et al. (1994) Tumor spectrum analysis in p53-mutant mice. Curr Biol 4: 1–7.

80. ElsonA, WangY, DaughertyCJ, MortonCC, ZhouF, et al. (1996) Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc Natl Acad Sci U S A 93: 13084–13089.

81. ShimaN, MunroeRJ, SchimentiJC (2004) The mouse genomic instability mutation chaos1 is an allele of Polq that exhibits genetic interaction with Atm. Mol Cell Biol 24: 10381–10389.

82. ReinholdtLG, MunroeRJ, KamdarS, SchimentiJC (2006) The mouse gcd2 mutation causes primordial germ cell depletion. Mech Dev 123: 559–569.

83. GinsburgM, SnowMH, McLarenA (1990) Primordial germ cells in the mouse embryo during gastrulation. Development 110: 521–528.

84. TakuboK, HiraoA, OhmuraM, AzumaM, AraiF, et al. (2006) Premeiotic germ cell defect in seminiferous tubules of Atm-null testis. Biochem Biophys Res Commun 351: 993–998.