The maintenance of genome stability is essential for the accurate transmission of genetic information, to ensure the successful duplication of chromosomes and their even segregation during mitosis. Errors occurring during DNA replication may affect both the accuracy of chromosome duplication and the balance of chromosome segregation during mitosis. Accurate DNA replication is strongly dependent on deoxynucleotides (dNTP) concentrations. Distortions in dNTP pool affect the rate of replication fork progression and compromise genetic stability. In the work presented here, we identified a novel mechanism by which dNTP pool disequilibrium compromises the completion of DNA replication and thus chromosome segregation, independently of the rate of fork progression. This mechanism involves the intracellular accumulation of deoxycytidine due to cytidine deaminase (CDA) deficiency, inhibiting PARP-1 activity. These results have direct implications for Bloom syndrome (BS), a rare genetic disease combining susceptibility to cancer and genomic instability. BS cells also have a CDA defect, resulting in a high frequency of ultrafine anaphase bridges due entirely to dCTP-dependent PARP-1 inhibition. These data highlight new pathological consequences of the distortion of dNTP pools and reveal an unexpected role for PARP-1 in preventing the accumulation of excessive amounts of unreplicated DNA and chromosome segregation defects.
Vyšlo v časopise: Pyrimidine Pool Disequilibrium Induced by a Cytidine Deaminase Deficiency Inhibits PARP-1 Activity, Leading to the Under Replication of DNA. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005384 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005384
1. Hills S.A. & Diffley J.F. (2014) DNA replication and oncogene-induced replicative stress. Curr Biol 24, R435–444.
2. Lecona E. & Fernandez-Capetillo O. (2014) Replication stress and cancer: It takes two to tango. Exp Cell Res 329, 26–34.
3. Magdalou I., Lopez B.S., Pasero P. & Lambert S.A. (2014) The causes of replication stress and their consequences on genome stability and cell fate. Semin Cell Dev Biol 30, 154–164.
4. Mazouzi A., Velimezi G. & Loizou J.I. (2014) DNA replication stress: Causes, resolution and disease. Exp Cell Res 329, 85–93.
5. Le Tallec B. et al. (2014) Updating the mechanisms of common fragile site instability: how to reconcile the different views? Cell Mol Life Sci 71, 4489–4494.
6. Mankouri H.W., Huttner D. & Hickson I.D. (2013) How unfinished business from S-phase affects mitosis and beyond. Embo J 32, 2661–2671.
7. Lengauer C., Kinzler K.W. & Vogelstein B. (1998) Genetic instabilities in human cancers. Nature 396, 643–649.
8. Baumann C., Korner R., Hofmann K. & Nigg E.A. (2007) PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell 128, 101–114.
9. Chan K.L., North P.S. & Hickson I.D. (2007) BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges. Embo J 26, 3397–3409.
10. Chan K.L. & Hickson I.D. (2009) On the origins of ultra-fine anaphase bridges. Cell Cycle 8, 3065–3066.
11. Chan K.L., Palmai-Pallag T., Ying S. & Hickson I.D. (2009) Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat Cell Biol 11, 753–760.
12. Ying S. et al. (2013) MUS81 promotes common fragile site expression. Nat Cell Biol 15, 1001–1007.
13. Naim V. & Rosselli F. (2009) The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nat Cell Biol 11, 761–768.
14. Naim V. & Rosselli F. (2009) The FANC pathway and mitosis: a replication legacy. Cell Cycle 8, 2907–2911.
15. Germann S.M. et al. (2013) TopBP1/Dpb11 binds DNA anaphase bridges to prevent genome instability. J Cell Biol 204, 45–59.
16. Lahkim Bennani-Belhaj K. et al. (2010) The Bloom syndrome protein limits the lethality associated with RAD51 deficiency. Mol Cancer Res 8, 385–394.
17. Rouzeau S. et al. (2012) Bloom's syndrome and PICH helicases cooperate with topoisomerase IIalpha in centromere disjunction before anaphase. PLoS One 7, e33905.
18. Debatisse M., Le Tallec B., Letessier A., Dutrillaux B. & Brison O. (2012) Common fragile sites: mechanisms of instability revisited. Trends Genet 28, 22–32.
19. Letessier A. et al. (2011) Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470, 120–123.
20. German J. (1997) Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet 93, 100–106.
21. Ellis N.A. et al. (1995) The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83, 655–666.
22. Bartram C.R., Koske-Westphal T. & Passarge E. (1976) Chromatid exchanges in ataxia telangiectasia, Bloom syndrome, Werner syndrome, and xeroderma pigmentosum. Ann Hum Genet 40, 79–86.
23. Chan K.L. & Hickson I.D. (2011) New insights into the formation and resolution of ultra-fine anaphase bridges. Semin Cell Dev Biol 22, 906–912.
24. Rao V.A. et al. (2007) Endogenous gamma-H2AX-ATM-Chk2 checkpoint activation in Bloom's syndrome helicase deficient cells is related to DNA replication arrested forks. Mol Cancer Res 5, 713–724.
25. Chabosseau P. et al. (2011) Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome. Nat Commun 2, 368.
26. Nguyen G.H. et al. (2014) Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs. Proc Natl Acad Sci U S A.
27. Nygaard P. (1986) On the role of cytidine deaminase in cellular metabolism. Adv Exp Med Biol 195 Pt B, 415–420.
28. Tallis M., Morra R., Barkauskaite E. & Ahel I. (2013) Poly(ADP-ribosyl)ation in regulation of chromatin structure and the DNA damage response. Chromosoma 123, 79–90.
29. Stoller R.G., Myers C.E. & Chabner B.A. (1978) Analysis of cytidine deaminase and tetrahydrouridine interaction by use of ligand techniques. Biochem Pharmacol 27, 53–59.
30. Arlt M.F. & Glover T.W. (2010) Inhibition of topoisomerase I prevents chromosome breakage at common fragile sites. DNA Repair (Amst) 9, 678–689.
31. Hahn A.T., Jones J.T. & Meyer T. (2009) Quantitative analysis of cell cycle phase durations and PC12 differentiation using fluorescent biosensors. Cell Cycle 8, 1044–1052.
32. Neelsen K.J. et al. (2013) Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template. Genes Dev 27, 2537–2542.
33. Berti M. et al. (2013) Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat Struct Mol Biol 20, 347–354.
34. Ray Chaudhuri A. et al. (2012) Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat Struct Mol Biol 19, 417–423.
35. Bergoglio V. et al. (2013) DNA synthesis by Pol eta promotes fragile site stability by preventing under-replicated DNA in mitosis. J Cell Biol 201, 395–408.
36. Naim V., Wilhelm T., Debatisse M. & Rosselli F. (2013) ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. Nat Cell Biol 15, 1008–1015.
37. Ramirez O., Garcia A., Rojas R., Couve A. & Hartel S. (2010) Confined displacement algorithm determines true and random colocalization in fluorescence microscopy. J Microsc 239, 173–183.
38. Zhang Y.W. et al. (2011) Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells. Nucleic Acids Res 39, 3607–3620.
39. Jungmichel S. et al. (2013) Proteome-wide identification of poly(ADP-Ribosyl)ation targets in different genotoxic stress responses. Mol Cell 52, 272–285.
40. Altmeyer M. et al. (2013) The chromatin scaffold protein SAFB1 renders chromatin permissive for DNA damage signaling. Mol Cell 52, 206–220.
41. Burkle A. & Virag L. (2013) Poly(ADP-ribose): PARadigms and PARadoxes. Mol Aspects Med 34, 1046–1065.
42. Kraus W.L. & Hottiger M.O. (2013) PARP-1 and gene regulation: progress and puzzles. Mol Aspects Med 34, 1109–1123.
43. Boesten D.M. et al. (2013) Accelerated aging during chronic oxidative stress: a role for PARP-1. Oxid Med Cell Longev 2013, 680414.
44. Fong P.C. et al. (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361, 123–134.
45. Biard D.S. (2007) Untangling the relationships between DNA repair pathways by silencing more than 20 DNA repair genes in human stable clones. Nucleic Acids Res 35, 3535–3550.
46. Godon C. et al. (2008) PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility. Nucleic Acids Res 36, 4454–4464.
47. Ladner R.D. (2001) The role of dUTPase and uracil-DNA repair in cancer chemotherapy. Curr Protein Pept Sci 2, 361–370.
48. Olinski R., Jurgowiak M. & Zaremba T. (2010) Uracil in DNA—its biological significance. Mutat Res 705, 239–245.
49. Ke Y. et al. (2011) PICH and BLM limit histone association with anaphase centromeric DNA threads and promote their resolution. Embo J 30, 3309–3321.
50. Sugimura K., Takebayashi S., Taguchi H., Takeda S. & Okumura K. (2008) PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA. J Cell Biol 183, 1203–1212.
51. Zellweger R. et al. (2015) Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells. J Cell Biol 208, 563–579.
52. Bryant H.E. et al. (2009) PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. Embo J 28, 2601–2615.
53. Lin S.J. & Guarente L. (2003) Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr Opin Cell Biol 15, 241–246.
54. Zhang X. & Mathews C.K. (1995) Natural DNA precursor pool asymmetry and base sequence context as determinants of replication fidelity. J Biol Chem 270, 8401–8404.
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
