Advertisement

DNA Repair in Stem Cell Maintenance and Conversion to Cancer Stem Cells

  • S. L. Gerson
  • J. Reese
  • J. Kenyon
Conference paper
Part of the Springer Series on Biofilms book series (SCHERING FOUND, volume 2006/5)

Abstract

Genomic stability is essential for cell and organism longevity. Without genomic stability, replication errors and external stress as well as direct forms of DNA damage can induce mutations, which decrease cell survival, cause altered gene expression, and can lead to cellular transformation. All represent the antithesis of maintenance of normal stem cell function. We argue here that genomic stability is essential for stem cell maintenance and longevity. This concept is supported by human diseases associated with premature aging and animal models of DNA damage repair abnormalities all of which lead to abnormalities of stem cell survival. Furthermore, with competitive repopulation, hematopoietic stem cell survival can be assessed in the face of DNA repair defects, and results from these studies support the general conclusion that chemotherapy and other forms of DNA damage lead to stem cell failure syndromes and malignant transformation most commonly along the myeloid and lymphoid pathways. Thus one origin of the cancer stem cell phenotype is the inability to maintain genomic stability among the stem cell population leading to mutational alterations and transformation. Capturing stem cells at this transition point represents an exciting field of discovery possibly leading to early detection and therapeutic interventions.

Keywords

Stem Cell Mismatch Repair Nucleotide Excision Repair Microsatellite Instability Premature Aging 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

Supported in part by grants from the National Institutes of Health, 5P30-CA-043703 and 5R01-AG-024916, and the State of Ohio Third Frontier Program.

References

  1. Bender CF, Sikes ML, Sullivan R, Huye LE, Le Beau MM et al. (2002) Cancer predisposition and hematopoietic failure in Rad50(S/S) mice. Genes Dev 16:2237–2251CrossRefPubMedGoogle Scholar
  2. Buck D, Moshous D, de Chasseval R, Ma Y, le Deist F et al. (2006) Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. Eur J Immunol 36:224–235CrossRefPubMedGoogle Scholar
  3. Carreau M, Gan OI, Liu L, Doedens M, McKerlie C et al. (1998) Bone marrow failure in the Fanconi anemia group C mouse model after DNA damage. Blood 91:2737–2744PubMedGoogle Scholar
  4. Curia MC, Palmirotta R, Aceto G, Messerini L, Veri MC et al. (1999) Unbalanced germ-line expression of hMLH1 and hMSH2 alleles in hereditary nonpolyposis colorectal cancer. Cancer Res 59:3570–3575PubMedGoogle Scholar
  5. de Boer J, Hoeijmakers JH (2000) Nucleotide excision repair and human syndromes. Carcinogenesis 21:453–460CrossRefPubMedGoogle Scholar
  6. Fern L, Pallis M, Ian Carter G, Seedhouse C, Russell N, Byrne J (2004) Clonal haemopoiesis may occur after conventional chemotherapy and is associated with accelerated telomere shortening and defects in the NQO1 pathway; possible mechanisms leading to an increased risk of t-AML/MDS. Br J Haematol 126:63–71CrossRefPubMedGoogle Scholar
  7. Gennery AR (2006) Primary immunodeficiency syndromes associated with defective DNA double-strand break repair. Br Med Bull 77–78:71–85CrossRefPubMedGoogle Scholar
  8. Hansson J (1992) Inherited defects in DNA repair and susceptibility to DNA-damaging agents. Toxicol Lett 64–65 Spec No:141–148Google Scholar
  9. Hoeijmakers JH (1994) Human nucleotide excision repair syndromes: molecular clues to unexpected intricacies. Eur J Cancer 30A:1912–1921CrossRefPubMedGoogle Scholar
  10. Ishikawa T, Zhang SS, Qin X, Takahashi Y, Oda H et al. (2004) DNA repair and cancer: lessons from mutant mouse models. Cancer Sci 95:112–117CrossRefPubMedGoogle Scholar
  11. Kook H (2005) Fanconi anemia: current management. Hematology 10(1):108–110CrossRefPubMedGoogle Scholar
  12. Krichevsky S, Pawelec G, Gural A, Effros RB, Globerson A et al. (2004) Age related microsatellite instability in T cells from healthy individuals. Exp Gerontol 39:507–515CrossRefPubMedGoogle Scholar
  13. Kuramoto K, Ban S, Oda K, Tanaka H, Kimura A, Suzuki G (2002) Chromosomal instability and radiosensitivity in myelodysplastic syndrome cells. Leukemia 16:2253–2258CrossRefPubMedGoogle Scholar
  14. Lahav M, Uziel O, Kestenbaum M, Fraser A, Shapiro H et al. (2005) Nonmyeloablative conditioning does not prevent telomere shortening after allogeneic stem cell transplantation. Transplantation 80:969–976CrossRefPubMedGoogle Scholar
  15. Lindor NM, Jalal SM, VanDeWalker TJ, Cunningham JM, Dahl RJ, Thibodeau SN (1998) Search for chromosome instability in lymphocytes with germ-line mutations in DNA mismatch repair genes. Cancer Genet Cytogenet 104:48–51CrossRefPubMedGoogle Scholar
  16. Liu L, Markowitz S, Gerson SL (1996) Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea. Cancer Res 56:5375–5379PubMedGoogle Scholar
  17. Lockett KL, Snowhite IV, Hu JJ (2005) Nucleotide-excision repair and prostate cancer risk. Cancer Lett 220:125–135CrossRefPubMedGoogle Scholar
  18. Meira LB, Reis AM, Cheo DL, Nahari D, Burns DK, Friedberg EC (2001) Cancer predisposition in mutant mice defective in multiple genetic pathways: uncovering important genetic interactions. Mutat Res 477:51–58CrossRefPubMedGoogle Scholar
  19. Modrich P (2006) Mechanisms in eukaryotic mismatch repair. J Biol Chem 281:30305–30309CrossRefPubMedGoogle Scholar
  20. Prasher JM, Lalai AS, Heijmans-Antonissen C, Ploemacher RE, Hoeijmakers JH et al. (2005) Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1−/− mice. EMBO J 24:861–871CrossRefPubMedGoogle Scholar
  21. Prochazka M, Gaskins HR, Shultz LD, Leiter EH (1992) The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency. Proc Natl Acad Sci USA 89:3290–3294CrossRefPubMedGoogle Scholar
  22. Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA (2002) “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298:597–600CrossRefPubMedGoogle Scholar
  23. Reese JS, Liu L, Gerson SL (2003) Repopulating defect of mismatch repair-deficient hematopoietic stem cells. Blood 102:1626–1633CrossRefPubMedGoogle Scholar
  24. Shultz LD (1991) Hematopoiesis and models of immunodeficiency. Semin Immunol 3:397–408PubMedGoogle Scholar
  25. Tachibana A (2004) Genetic and physiological regulation of non-homologous end-joining in mammalian cells. Adv Biophys 38:21–44CrossRefGoogle Scholar
  26. van Steeg H, de Vries A, van Oostrom C, van Benthem J, Beems RB, van Kreijl CF (2001) DNA repair-deficient Xpa and Xpa/p53+/− knock-out mice: nature of the models. Toxicol Pathol 29:109–116CrossRefPubMedGoogle Scholar
  27. Yamashita T, Nakahata T (2001) Current knowledge on the pathophysiology of Fanconi anemia: from genes to phenotypes. Int J Hematol 74:33–41CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Case Comprehensive Cancer Center Division of Hematology/OncologyCase Western Reserve UniversityIreland Cancer Center, University Hospitals Case Medical CenterClevelandUSA

Personalised recommendations