Skip to main content
SpringerLink
Log in

Cell cycle checkpoints and DNA repair preserve the stability of the human genome

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Summary

Chemical carcinogenesis in the regenerating rat liver is cell-cycle-dependent. Proliferating hepatocytes were maximally susceptible to initiation by a single dose of benzo[a]pyrene diolepoxide I when at the G1/S border. Hepatocytes in early G1 or late S/G2/M were less susceptible and non-proliferating G0 hepatocytes were resistant to initiation. Radiation clastogenesis in proliferating human fibroblasts also is cell-cycle-dependent. Ultraviolet radiation (UV) induced maximal frequencies of chromosomal aberrations in synchronized cells that were at the G1/S border. Cells in early G1 or G2 were significantly less sensitive. For both initiation of chemical carcinogenesis and UV-clastogenesis, it appears that replication of damaged DNA is required and DNA repair before replication reduces cellular risk. If DNA repair is protective, cell cycle checkpoints which delay DNA replication and mitosis should augment this protective influence by providing more time for repair. The contribution of cell cycle checkpoint function to DNA repair during cell cycle-dependent clastogenesis was studied using ataxia telangiectasia (AT) fibroblasts. The AT cells displayed a defect in the coupling of DNA damage to checkpoints which control the G1/S and G2/M transitions and the rate of replicon initiation in S phase cells. UV-clastogenesis in AT cells was cell-cycle-dependent with irradiation at the G1/S boundary inducing 3-times more aberrations than treatment in G0 at the time of release into the cell cycle. Thus, DNA excision repair during the pre-replicative G1 phase was protective even in cells with defective checkpoint function. However, following irradiation at the G1/S border, AT cells displayed about 6-fold increased levels of UV-induced chromosome aberrations in comparison to normal human fibroblasts that were treated at this time. These observations indicate that secondary and tertiary DNA lesions that are produced during replication of UV-damaged DNA (replicative gaps and double-strand breaks) also depend on checkpoint function for repair. The replicon initiation and G2-delay checkpoints that operate after initiation of S phase appear to play a major role in protection against UV-clastogenesis.

‘DNA is, in fact, so precious and so fragile that we now know that the cell has evolved a whole variety of repair mechanisms to protect its DNA from assaults by radiation, chemicals, and other hazards. This is exactly the sort of thing that the process of evolution by natural selection would lead us to expect.’ Francis Crick inWhat Mad Pursuit

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Freidberg EC:DNA Repair, Plenum Press, NY 1986

    Google Scholar 

  2. Kraemer KH: Heritable diseases with increased sensitivity to cellular injury.In: Fitzpatrick, Eisen, Wolff, Freedberg, Austen (eds) Dermatology in General Medicine. McGraw Hill, NY 1987, Chapter 50

    Google Scholar 

  3. Painter RB, Young BR: Formation of nascent DNA molecules during inhibition of replicon initiation in mammalian cells. Biochim Biophys Acta 418: 146–153, 1976

    Google Scholar 

  4. Thony B, Hwang DS, Fradkin L, Kornberg A:iciA, anEscherichia coli gene encloding a specific inhibitor of chromosomal initiation of replicationin vitro. Proc Natl Acad Sci USA 88: 4066–4070, 1991

    Google Scholar 

  5. Barrett JC, Oshimura M, Koi M: Role of oncogenes and tumor suppressor genes in a multistep model of carcinogenesis.In: Beckeriand FF, Slaga TJ (eds) Critical Molecular Determinants of Carcinogenesis. Univ. of Texas Press, Austin TX, 45–56, 1987

    Google Scholar 

  6. Nettesheim P, Barrett JC: Tracheal epithelial cell transformation: A model system for studies on neoplastic progression. CRC Crit Rev Toxicol 12: 215–240, 1984

    Google Scholar 

  7. Hartwell L: Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71: 543–546, 1992

    Google Scholar 

  8. Kaufmann WK, Kaufman DG: Cell cycle control, DNA repair and initiation of carcinogenesis. FASEB J 7: 1188–1191, 1993

    Google Scholar 

  9. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW: Participation of p53 protein in the cellular responses to DNA damage. Cancer Res 51: 6304–6311, 1991

    Google Scholar 

  10. Dulic V, Kaufmann WK, Wilson SJ, Tlsty TD, Lees E, Harper JW, Elledge SJ, Reed SI: p53-Dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 76: 1013–1023, 1994

    Google Scholar 

  11. Yin Y, Tainsky MA, Bischoff FZ, Strong LC, Wahl GM: Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70: 937–948, 1992

    Google Scholar 

  12. Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD: Altered cell cycle arrest and gene amplification potential accompany loss of wild type p53. Cell 70: 923–935, 1992

    Google Scholar 

  13. Kaufmann WK, Rice JM, Wenk ML, Devor D, Kaufman DG: Cell cycle-dependent initiation of hepatocarcinogenesis in rats by methyl(acetoxymethyl)nitrosamine. Cancer Res 47: 1263–1266, 1987

    Google Scholar 

  14. Kaufman WK, Rahija RJ, MacKenzie SA, Kaufman DG: Cell cycle-dependent initiation of hepatocarcinogenesis in rats by (±)- 7r,8t-dihydroxy- 9t,10t-epoxy- 7,8,9,10-tetrahy-drobenzo[a]pyrene. Cancer Res 47: 3771–3775, 1987

    Google Scholar 

  15. Nowell PC, Croce CM: Chromosomes, genes and cancer. Am J Pathol 125: 7–15, 1986

    Google Scholar 

  16. Kaufmann WK, Wilson SJ: G1 arrest and cell cycle-dependent clastogenesis in UV-irradiated human fibroblasts. Mutat Res 314: 67–76, 1994

    Google Scholar 

  17. Kaufmann WK, Wilson SR: DNA repair endonuclease activity during synchronous proliferation of diploid human fibroblasts. Mutat Res 236: 107–117, 1990

    Google Scholar 

  18. Cohen MM, Levy HP: Chromosomal instability syndromes. Adv Human Genet 18: 43–149, 1989

    Google Scholar 

  19. Kastan MB, Zhan Q, El-Deirey WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace AJ, Jr: A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia telangiectasia. Cell 71: 587–597, 1992

    Google Scholar 

  20. El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Wiman KG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW, Vogelstein B: WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54: 1169–1174, 1994

    Google Scholar 

  21. Kaufmann WK, Cleaver JE: Mechanisms of inhibition of DNA replication by ultraviolet light in normal human and xeroderma pigmentosum fibroblasts. J Mol Biol 149: 171–187, 1981

    Google Scholar 

  22. Kaufmann WK, Boyer JC, Smith BA, Cordeiro-Stone M: DNA repair and replication in human fibroblasts treated with (±)r-7,t-8-dihydroxy-t-9,10- epoxy-7,8,9,10- tetrahy-drobenzo[a]pyrene. Biochim Biophys Acta 824: 146–151, 1985

    Google Scholar 

  23. Kaufmann WK, Boyer JC, Estabrooks LE, Wilson SR: Inhibition of replicon initiation in human cells following transient stabilization of topoisomerase-DNA complexes. Mol Cell Biol 11: 3711–3718, 1991

    Google Scholar 

  24. Painter RB, Young BR: Radiosensitivity in ataxia telangiectasia: a new explanation. Proc Natl Acad Sci USA 77: 7315–7317, 1980

    Google Scholar 

  25. Painter RB: Inhibition and recovery of DNA synthesis in human cells after exposure to ultraviolet light. Mutation Res 145: 63–69, 1985

    Google Scholar 

  26. Kaufmann WK: Pathways of human cell postreplication repair. Carcinogenesis 10: 1–11, 1989

    Google Scholar 

  27. Boyer JC, Kaufmann WK, Cordeiro-Stone M: Role of postreplication repair in transformation of human fibroblasts to anchorage independence. Cancer Res 51: 2960–2964, 1991

    Google Scholar 

  28. O'Connor PM, Ferris DK, Pagano M, Draetta G, Pines J, Hunter T, Longo DL, Kohn KW: G2 delay induced by nitrogen mustard in human cells affects cyclin A/cdk2 and cyclin B/cdc2 complexes differently. J Biol Chem 268: 8298–8308, 1993

    Google Scholar 

  29. Olivieri G, Micheli A: Mitotic delay and repair in human lymphocytes. Mutat Res 122: 65–72, 1983

    Google Scholar 

  30. Zampetti-Bosseler F, Scott D: Cell death, chromosome damage, and mitotic delay in normal human, ataxia telangiectasia and retinoblastoma fibroblasts after X-irradiation. Inter J Radiat Biol 39: 547–558, 1981

    Google Scholar 

  31. Bender MA, Rary JM, Kale PR: G2 chromosomal radiosensitivity in ataxia-telangiectasia lymphocytes. Mutat Res 152: 39–47, 1985

    Google Scholar 

  32. Taylor AMR: Unrepaired DNA strand breaks in irradiated ataxia telangiectasia lymphocytes suggested from cytogenetic observations. Mutat Res 50: 407–418, 1978

    Google Scholar 

  33. Ejima Y, Sasaki MS: Enhanced expression of X-ray- and UV-induced chromosome aberrations by cytosine arabinoside in ataxia telangiectasia cells. Mutat Res 159: 117–123, 1986

    Google Scholar 

  34. Watanabe M, Maher VM, McCormick JJ: Excision repair of UV-of benzo[a]pyrene diolepoxide-induced lesions in xeroderma pigmentosum variant cells is ‘error-free’. Mutat Res 146: 285–294, 1985

    Google Scholar 

  35. Bender MA, Griggs HG, Walker PL: Mechanisms of chromosomal aberration production. I. Aberration induction by ultraviolet light. Mutat Res 20: 387–402, 1973

    Google Scholar 

  36. Wang TCV, Smith KC: Postreplication repair in ultraviolet-irradiated human fibroblasts: formation and repair of DNA double strand breaks. Carcinogenesis 7: 389–392, 1986

    Google Scholar 

  37. Darroudi F, Natarajan AT, van der Schans GP: Biochemical and cytogenetical characterization of Chinese hamster ovary X-ray-sensitive mutant cells xrs 5 and xrs 6. VI. The correlation between UV-induced DNA lesions and chromosomal aberrations, and their modulations with inhibitors of DNA repair synthesis. Mutat Res 235: 129–135, 1990

    Google Scholar 

  38. Dulic V, Drullinger LF, Lees E, Reed SI, Stein GH: Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin D1/Cdk2 and cyclin E/Cdk2 complexes. Proc Natl Acad Sci USA 90: 11034–11038, 1993

    Google Scholar 

  39. Allsop RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB: Telomere length predicts the replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 89: 10114–10118, 1992

    Google Scholar 

  40. Kaufmann WK, Rice JM, MacKenzie SA, Smith GJ, Wenk ML, Devor D, Qaqish BF, Kaufman DG: Proliferation of carcinogen-damaged hepatocytes during cell-cycle-dependent initiation of hepatocarcinogenesis in the rat. Carcinogenesis 12: 1587–1593, 1991

    Google Scholar 

  41. Goldmacher VS, Cuzick RA Jr, Thilly WG: Isolation and partial characterization of human cell mutants differing in sensitivity to killing and mutation by methylnitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine. J Biol Chem 261: 12642–12471, 1986

    Google Scholar 

  42. Kat A, Thilly WG, Fang W-H, Longley MJ, Li G-M, Modrich P: An alkylation-tolerant mutator human cell line is deficient in strand-specific mismatch repair. Proc Natl Acad Sci USA 90: 6424–6428, 1993

    Google Scholar 

  43. Umar A, Boyer JC, Thomas DC, Nguyen DC, Risinger JI, Boyd J, Ionov Y, Perucho M, Kunkel TA: Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J Biol Chem 269: 14367–14370, 1994

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CB #7295, Department of Pathology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599-7295, North Carolina, USA

    William K. Kaufmann

Authors
  1. William K. Kaufmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaufmann, W.K. Cell cycle checkpoints and DNA repair preserve the stability of the human genome. Cancer Metast Rev 14, 31–41 (1995). https://doi.org/10.1007/BF00690209

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00690209

Key words

Search

Navigation