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A Role for the Malignant Brain Tumour (MBT) Domain Protein LIN-61 in DNA Double-Strand Break Repair by Homologous Recombination


Malignant brain tumour (MBT) domain proteins are transcriptional repressors that function within Polycomb complexes. Some MBT genes are tumour suppressors, but how they prevent tumourigenesis is unknown. The Caenorhabditis elegans MBT protein LIN-61 is a member of the synMuvB chromatin-remodelling proteins that control vulval development. Here we report a new role for LIN-61: it protects the genome by promoting homologous recombination (HR) for the repair of DNA double-strand breaks (DSBs). lin-61 mutants manifest numerous problems associated with defective HR in germ and somatic cells but remain proficient in meiotic recombination. They are hypersensitive to ionizing radiation and interstrand crosslinks but not UV light. Using a novel reporter system that monitors repair of a defined DSB in C. elegans somatic cells, we show that LIN-61 contributes to HR. The involvement of this MBT protein in HR raises the possibility that MBT–deficient tumours may also have defective DSB repair.


Vyšlo v časopise: A Role for the Malignant Brain Tumour (MBT) Domain Protein LIN-61 in DNA Double-Strand Break Repair by Homologous Recombination. PLoS Genet 9(3): e32767. doi:10.1371/journal.pgen.1003339
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003339

Souhrn

Malignant brain tumour (MBT) domain proteins are transcriptional repressors that function within Polycomb complexes. Some MBT genes are tumour suppressors, but how they prevent tumourigenesis is unknown. The Caenorhabditis elegans MBT protein LIN-61 is a member of the synMuvB chromatin-remodelling proteins that control vulval development. Here we report a new role for LIN-61: it protects the genome by promoting homologous recombination (HR) for the repair of DNA double-strand breaks (DSBs). lin-61 mutants manifest numerous problems associated with defective HR in germ and somatic cells but remain proficient in meiotic recombination. They are hypersensitive to ionizing radiation and interstrand crosslinks but not UV light. Using a novel reporter system that monitors repair of a defined DSB in C. elegans somatic cells, we show that LIN-61 contributes to HR. The involvement of this MBT protein in HR raises the possibility that MBT–deficient tumours may also have defective DSB repair.


Zdroje

1. TremethickDJ (2007) Higher-order structures of chromatin: the elusive 30 nm fiber. Cell 128: 651–654 doi:10.1016/j.cell.2007.02.008.

2. KouzaridesT (2007) Chromatin modifications and their function. Cell 128: 693–705 doi:10.1016/j.cell.2007.02.005.

3. TrojerP, LiG, SimsRJ, VaqueroA, KalakondaN, et al. (2007) L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129: 915–928 doi:10.1016/j.cell.2007.03.048.

4. BonasioR, LeconaE, ReinbergD (2010) MBT domain proteins in development and disease. Semin Cell Dev Biol 21: 221–230 doi:10.1016/j.semcdb.2009.09.010.

5. SafferAM, KimDH, van OudenaardenA, HorvitzHR (2011) The Caenorhabditis elegans Synthetic Multivulva Genes Prevent Ras Pathway Activation by Tightly Repressing Global Ectopic Expression of lin-3 EGF. PLoS Genet 7: e1002418 doi:10.1371/journal.pgen.1002418.

6. HarrisonMM, LuX, HorvitzHR (2007) LIN-61, one of two Caenorhabditis elegans malignant-brain-tumor-repeat-containing proteins, acts with the DRM and NuRD-like protein complexes in vulval development but not in certain other biological processes. Genetics 176: 255–271 doi:10.1534/genetics.106.069633.

7. PoulinG, DongY, FraserAG, HopperNA, AhringerJ (2005) Chromatin regulation and sumoylation in the inhibition of Ras-induced vulval development in Caenorhabditis elegans. EMBO J 24: 2613–2623 doi:10.1038/sj.emboj.7600726.

8. PothofJ, van HaaftenG, ThijssenK, KamathRS, FraserAG, et al. (2003) Identification of genes that protect the C. elegans genome against mutations by genome-wide RNAi. Genes Dev 17: 443–448 doi:10.1101/gad.1060703.

9. WismarJ, LöfflerT, HabtemichaelN, VefO, GeissenM, et al. (1995) The Drosophila melanogaster tumor suppressor gene lethal(3)malignant brain tumor encodes a proline-rich protein with a novel zinc finger. Mech Dev 53: 141–154.

10. NorthcottPA, NakaharaY, WuX, FeukL, EllisonDW, et al. (2009) Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet 41: 465–472 doi:10.1038/ng.336.

11. GurvichN, PernaF, FarinaA, VozaF, MenendezS, et al. (2010) L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability. Proc Natl Acad Sci USA 107: 22552–22557 doi:10.1073/pnas.1017092108.

12. JanicA, MendizabalL, LlamazaresS, RossellD, GonzalezC (2010) Ectopic Expression of Germline Genes Drives Malignant Brain Tumor Growth in Drosophila. Science 330: 1824–1827 doi:10.1126/science.1195481.

13. PetrellaLN, WangW, SpikeCA, RechtsteinerA, ReinkeV, et al. (2011) synMuv B proteins antagonize germline fate in the intestine and ensure C. elegans survival. Development 138: 1069–1079 doi:10.1242/dev.059501.

14. LuijsterburgMS, van AttikumH (2011) Chromatin and the DNA damage response: The cancer connection. Mol Oncol doi:10.1016/j.molonc.2011.06.001.

15. Koester-EiserfunkeN, FischleW (2011) H3K9me2/3 binding of the MBT domain protein LIN-61 is essential for Caenorhabditis elegans vulva development. PLoS Genet 7: e1002017 doi:10.1371/journal.pgen.1002017.

16. YoudsJL, O'NeilNJ, RoseAM (2006) Homologous recombination is required for genome stability in the absence of DOG-1 in Caenorhabditis elegans. Genetics 173: 697–708 doi:10.1534/genetics.106.056879.

17. GrabowskiMM, SvrzikapaN, TissenbaumHA (2005) Bloom syndrome ortholog HIM-6 maintains genomic stability in C. elegans. Mech Ageing Dev 126: 1314–1321 doi:10.1016/j.mad.2005.08.005.

18. YanowitzJL (2008) Genome integrity is regulated by the Caenorhabditis elegans Rad51D homolog rfs-1. Genetics 179: 249–262 doi:10.1534/genetics.107.076877.

19. BickelJS, ChenL, HaywardJ, YeapSL, AlkersAE, et al. (2010) Structural maintenance of chromosomes (SMC) proteins promote homolog-independent recombination repair in meiosis crucial for germ cell genomic stability. PLoS Genet 6: e1001028 doi:10.1371/journal.pgen.1001028.

20. AlpiA, PasierbekP, GartnerA, LoidlJ (2003) Genetic and cytological characterization of the recombination protein RAD-51 in Caenorhabditis elegans. Chromosoma 112: 6–16 doi:10.1007/s00412-003-0237-5.

21. WardJD, BarberLJ, PetalcorinMI, YanowitzJ, BoultonSJ (2007) Replication blocking lesions present a unique substrate for homologous recombination. EMBO J 26: 3384–3396 doi:10.1038/sj.emboj.7601766.

22. HayashiM, ChinGM, VilleneuveAM (2007) C. elegans germ cells switch between distinct modes of double-strand break repair during meiotic prophase progression. PLoS Genet 3: e191 doi:10.1371/journal.pgen.0030191.

23. DernburgAF, McDonaldK, MoulderG, BarsteadR, DresserM, et al. (1998) Meiotic recombination in C. elegans initiates by a conserved mechanism and is dispensable for homologous chromosome synapsis. Cell 94: 387–398.

24. ColaiácovoMP, MacQueenAJ, Martinez-PerezE, McDonaldK, AdamoA, et al. (2003) Synaptonemal complex assembly in C. elegans is dispensable for loading strand-exchange proteins but critical for proper completion of recombination. Dev Cell 5: 463–474.

25. HodgkinJ, HorvitzHR, BrennerS (1979) Nondisjunction Mutants of the Nematode CAENORHABDITIS ELEGANS. Genetics 91: 67–94.

26. BoultonSJ, MartinJS, PolanowskaJ, HillDE, GartnerA, et al. (2004) BRCA1/BARD1 orthologs required for DNA repair in Caenorhabditis elegans. Current Biology 14: 33–39.

27. AdamoA, MontemauriP, SilvaN, WardJD, BoultonSJ, et al. (2008) BRC-1 acts in the inter-sister pathway of meiotic double-strand break repair. EMBO Rep 9: 287–292 doi:10.1038/sj.embor.7401167.

28. DeansAJ, WestSC (2011) DNA interstrand crosslink repair and cancer. Nat Rev Cancer 11: 467–480 doi:10.1038/nrc3088.

29. LongDT, RäschleM, JoukovV, WalterJC (2011) Mechanism of RAD51-dependent DNA interstrand cross-link repair. Science 333: 84–87 doi:10.1126/science.1204258.

30. CicciaA, ElledgeSJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40: 179–204 doi:10.1016/j.molcel.2010.09.019.

31. RoerinkSF, KooleW, StapelLC, RomeijnRJ, TijstermanM (2012) A Broad Requirement for TLS Polymerases η and κ, and Interacting Sumoylation and Nuclear Pore Proteins, in Lesion Bypass during C. elegans Embryogenesis. PLoS Genet 8: e1002800 doi:10.1371/journal.pgen.1002800.

32. ClejanI, BoerckelJ, AhmedS (2006) Developmental modulation of nonhomologous end joining in Caenorhabditis elegans. Genetics 173: 1301–1317 doi:10.1534/genetics.106.058628.

33. JacksonSP, BartekJ (2009) The DNA-damage response in human biology and disease. Nature 461: 1071–1078 doi:10.1038/nature08467.

34. KipreosET (2005) C. elegans cell cycles: invariance and stem cell divisions. Nat Rev Mol Cell Biol 6: 766–776 doi:10.1038/nrm1738.

35. EdgarLG, McGheeJD (1988) DNA synthesis and the control of embryonic gene expression in C. elegans. Cell 53: 589–599.

36. BaillyAP, FreemanA, HallJ, DéclaisA-C, AlpiA, et al. (2010) The Caenorhabditis elegans homolog of Gen1/Yen1 resolvases links DNA damage signaling to DNA double-strand break repair. PLoS Genet 6: e1001025 doi:10.1371/journal.pgen.1001025.

37. KriskoA, RadmanM (2010) Protein damage and death by radiation in Escherichia coli and Deinococcus radiodurans. Proc Natl Acad Sci USA 107: 14373–14377 doi:10.1073/pnas.1009312107.

38. PierceAJ, JohnsonRD, ThompsonLH, JasinM (1999) XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev 13: 2633–2638.

39. HelledayT, LoJ, van GentDC, EngelwardBP (2007) DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair 6: 923–935 doi:10.1016/j.dnarep.2007.02.006.

40. HedgecockEM, WhiteJG (1985) Polyploid tissues in the nematode Caenorhabditis elegans. Dev Biol 107: 128–133.

41. PontierDB, TijstermanM (2009) A robust network of double-strand break repair pathways governs genome integrity during C. elegans development. Current biology: CB 19: 1384–1388 doi:10.1016/j.cub.2009.06.045.

42. YoudsJL, MetsDG, McIlwraithMJ, MartinJS, WardJD, et al. (2010) RTEL-1 enforces meiotic crossover interference and homeostasis. Science 327: 1254–1258 doi:10.1126/science.1183112.

43. 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.

44. MoserSC, Elsner vonS, BüssingI, AlpiA, SchnabelR, et al. (2009) Functional dissection of Caenorhabditis elegans CLK-2/TEL2 cell cycle defects during embryogenesis and germline development. PLoS Genet 5: e1000451 doi:10.1371/journal.pgen.1000451.

45. SchumacherB, HofmannK, BoultonS, GartnerA (2001) The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. Current biology: CB 11: 1722–1727.

46. ConradtB, HorvitzHR (1998) The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93: 519–529.

47. HillersKJ, VilleneuveAM (2003) Chromosome-wide control of meiotic crossing over in C. elegans. Current biology: CB 13: 1641–1647 doi:10.1016/j.cub.2003.08.026.

48. MillerKM, TjeertesJV, CoatesJ, LegubeG, PoloSE, et al. (2010) Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat Struct Mol Biol doi:10.1038/nsmb.1899.

49. SmeenkG, WiegantWW, VrolijkH, SolariAP, PastinkA, et al. (2010) The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage. J Cell Biol 190: 741–749 doi:10.1083/jcb.201001048.

50. ChouDM, AdamsonB, DephoureNE, TanX, NottkeAC, et al. (2010) A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proc Natl Acad Sci USA 107: 18475–18480 doi:10.1073/pnas.1012946107.

51. FacchinoS, AbdouhM, ChatooW, BernierG (2010) BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci 30: 10096–10111 doi:10.1523/JNEUROSCI.1634-10.2010.

52. GinjalaV, NacerddineK, KulkarniA, OzaJ, HillSJ, et al. (2011) BMI1 is recruited to DNA breaks and contributes to DNA damage-induced H2A ubiquitination and repair. Mol Cell Biol 31: 1972–1982 doi:10.1128/MCB.00981-10.

53. LuijsterburgMS, DinantC, LansH, StapJ, WiernaszE, et al. (2009) Heterochromatin protein 1 is recruited to various types of DNA damage. J Cell Biol 185: 577–586 doi:10.1083/jcb.200810035.

54. IsmailIH, AndrinC, McDonaldD, HendzelMJ (2010) BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. J Cell Biol 191: 45–60 doi:10.1083/jcb.201003034.

55. PanM-R, PengG, HungW-C, LinS-Y (2011) Monoubiquitination of H2AX Protein Regulates DNA Damage Response Signaling. J Biol Chem 286: 28599–28607 doi:10.1074/jbc.M111.256297.

56. TrojerP, CaoAR, GaoZ, LiY, ZhangJ, et al. (2011) L3MBTL2 protein acts in concert with PcG protein-mediated monoubiquitination of H2A to establish a repressive chromatin structure. Mol Cell 42: 438–450 doi:10.1016/j.molcel.2011.04.004.

57. IacovoniJS, CaronP, LassadiI, NicolasE, MassipL, et al. (2010) High-resolution profiling of gammaH2AX around DNA double strand breaks in the mammalian genome. EMBO J 29: 1446–1457 doi:10.1038/emboj.2010.38.

58. ShanbhagNM, Rafalska-MetcalfIU, Balane-BolivarC, JanickiSM, GreenbergRA (2010) ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell 141: 970–981 doi:10.1016/j.cell.2010.04.038.

59. BrennerS (1974) The genetics of Caenorhabditis elegans. Genetics 77: 71–94.

60. HofmannER, MilsteinS, BoultonSJ, YeM, HofmannJJ, et al. (2002) Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis. Current Biology 12: 1908–1918.

61. BarberLJ, YoudsJL, WardJD, McIlwraithMJ, O'NeilNJ, et al. (2008) RTEL1 maintains genomic stability by suppressing homologous recombination. Cell 135: 261–271 doi:10.1016/j.cell.2008.08.016.

62. PolanowskaJ, MartinJS, Garcia-MuseT, PetalcorinMIR, BoultonSJ (2006) A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites. EMBO J 25: 2178–2188 doi:10.1038/sj.emboj.7601102.

63. DmitrievaNI, CelesteA, NussenzweigA, BurgMB (2005) Ku86 preserves chromatin integrity in cells adapted to high NaCl. Proc Natl Acad Sci USA 102: 10730–10735 doi:10.1073/pnas.0504870102.

64. SaitoTT, YoudsJL, BoultonSJ, ColaiácovoMP (2009) Caenorhabditis elegans HIM-18/SLX-4 interacts with SLX-1 and XPF-1 and maintains genomic integrity in the germline by processing recombination intermediates. PLoS Genet 5: e1000735 doi:10.1371/journal.pgen.1000735.

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