Skip to main content
Log in

Age-dependent down-regulation of DNA polymerase δ1 in human lymphocytes

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Aging progress and degeneracy of functional activity are mainly attributed to the decreased DNA repair potential. DNA polymerase (pol) δ activity plays an essential role in genome stability by virtue of its crucial DNA replication and repair capacity. To order to clarify the role of DNA pol δ in aging progression, we firstly examined the expressions of its catalytic subunit named DNA pol δ1 in human lymphocytes at different age stages, respectively, and then observed the effect of diseases on DNA pol δ1 in vivo and of nutriture on its expressions in 2BS cells in vitro. Blood samples from the healthy subjects and patients with diabetes mellitus and coronary heart disease were collected, respectively, for analysis of transcription and protein expressions of DNA pol δ1 by RT-PCR and western blot. 2BS cells of PD30 and PD47 were incubated in both normal medium and other mediums of different nutritures for verifying the differential expressions of DNA pol δ1. Results showed that the mRNA expression of DNA pol δ1 decreased substantially with age and the protein levels were well consistent with gene levels. Furthermore, there were no significant differences in DNA pol δ1 expressions between the groups of healthy individuals and the age matched patients. In addition, DNA pol δ1 gene expression levels were not affected by nutritional status in vitro. Our findings collectively confirmed that the down-regulations of DNA pol δ1 are age-related and have little bearing on diseases and nutritures. DNA pol δ1 has great potential for a new biomarker of aging.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 11:567–578. doi:10.1038/nrm2944

    Article  PubMed  CAS  Google Scholar 

  2. Zhang JH, Zhang Y, Herman B (2003) Caspases, apoptosis and aging. Ageing Res Rev 2:357–366

    Article  PubMed  CAS  Google Scholar 

  3. Behrens MI, Silva M, Schmied A, Salech F, Manzur H, Rebolledo R, Bull R, Torres V, Henriquez M, Quest AF (2011) Age-dependent increases in apoptosis/necrosis ratios in human lymphocytes exposed to oxidative stress. J Gerontol A Biol Sci Med Sci 66:732–740. doi:10.1093/gerona/glr039

    Article  PubMed  Google Scholar 

  4. Mather KA, Jorm AF, Parslow RA, Christensen H (2011) Is telomere length a biomarker of aging? A review. J Gerontol A Biol Sci Med Sci 66:202–213. doi:10.1093/gerona/glq180

    Article  PubMed  Google Scholar 

  5. Johnson TE (2006) Recent results: biomarkers of aging. Exp Gerontol 41:1243–1246. doi:10.1016/j.exger.2006.09.006

    Article  PubMed  CAS  Google Scholar 

  6. Ma H, Li R, Zhang Z, Tong T (2004) mRNA level of alpha-2-macroglobulin as an aging biomarker of human fibroblasts in culture. Exp Gerontol 39:415–421. doi:10.1016/j.exger.2003.11.012

    Article  PubMed  CAS  Google Scholar 

  7. Sloane LB, Stout JT, Austad SN, McClearn GE (2011) Tail tendon break time: a biomarker of aging? J Gerontol A Biol Sci Med Sci 66:287–294. doi:10.1093/gerona/glq196

    Article  PubMed  Google Scholar 

  8. Wang JL, Wang PC (2012) The effect of aging on the DNA damage and repair capacity in 2BS cells undergoing oxidative stress. Mol Biol Rep 39:233–241. doi:10.1007/s11033-011-0731-4

    Article  PubMed  CAS  Google Scholar 

  9. Takahashi Y, Moriwaki S, Sugiyama Y, Endo Y, Yamazaki K, Mori T, Takigawa M, Inoue S (2005) Decreased gene expression responsible for post-ultraviolet DNA repair synthesis in aging: a possible mechanism of age-related reduction in DNA repair capacity. J Invest Dermatol 124:435–442. doi:10.1111/j.0022-202X.2004.23591.x

    Article  PubMed  CAS  Google Scholar 

  10. Kamath-Loeb AS, Johansson E, Burgers PM, Loeb LA (2000) Functional interaction between the Werner Syndrome protein and DNA polymerase delta. Proc Natl Acad Sci USA 97:4603–4608

    Article  PubMed  CAS  Google Scholar 

  11. Szekely AM, Chen YH, Zhang C, Oshima J, Weissman SM (2000) Werner protein recruits DNA polymerase delta to the nucleolus. Proc Natl Acad Sci USA 97:11365–11370. doi:10.1073/pnas.97.21.11365

    Article  PubMed  CAS  Google Scholar 

  12. Liu L, Mo J, Rodriguez-Belmonte EM, Lee MY (2000) Identification of a fourth subunit of mammalian DNA polymerase delta. J Biol Chem 275:18739–18744. doi:10.1074/jbc.M001217200

    Article  PubMed  CAS  Google Scholar 

  13. Sanefuji K, Taketomi A, Iguchi T, Sugimachi K, Ikegami T, Yamashita Y, Gion T, Soejima Y, Shirabe K, Maehara Y (2010) Significance of DNA polymerase delta catalytic subunit p125 induced by mutant p53 in the invasive potential of human hepatocellular carcinoma. Oncology 79:229–237. doi:10.1159/000322374

    Article  PubMed  CAS  Google Scholar 

  14. Brocas C, Charbonnier JB, Dherin C, Gangloff S, Maloisel L (2010) Stable interactions between DNA polymerase delta catalytic and structural subunits are essential for efficient DNA repair. DNA Repair (Amst) 9:1098–1111. doi:10.1016/j.dnarep.2010.07.013

    Article  CAS  Google Scholar 

  15. Villani G, Hubscher U, Gironis N, Parkkinen S, Pospiech H, Shevelev I, di Cicco G, Markkanen E, Syvaoja JE, Tanguy Le Gac N (2011) In vitro gap-directed translesion DNA synthesis of an abasic site involving human DNA polymerases epsilon, lambda, and beta. J Biol Chem 286:32094–32104. doi:10.1074/jbc.M111.246611

    Article  PubMed  CAS  Google Scholar 

  16. Kunkel TA, Burgers PM (2008) Dividing the workload at a eukaryotic replication fork. Trends Cell Biol 18:521–527. doi:10.1016/j.tcb.2008.08.005

    Article  PubMed  CAS  Google Scholar 

  17. Czechowska A, Blasiak J (2005) Eukaryotic DNA polymerases. Postepy Biochem 51:130–139

    PubMed  CAS  Google Scholar 

  18. Basevi V, Di Mario S, Morciano C, Nonino F, Magrini N (2011) Comment on: American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(Suppl. 1):S11–S61. Diabetes Care 34:e53. doi:10.2337/dc11-0174 (author reply e54)

    Article  PubMed  Google Scholar 

  19. American Diabetes Association (2011) Diagnosis and classification of diabetes mellitus. Diabetes Care 34(Suppl 1):S62–S69. doi:10.2337/dc11-S062

    Article  Google Scholar 

  20. Cameron SJ, Sokoll LJ, Laterza OF, Shah S, Green GB (2007) A multi-marker approach for the prediction of adverse events in patients with acute coronary syndromes. Clin Chim Acta 376:168–173. doi:10.1016/j.cca.2006.08.019

    Article  PubMed  CAS  Google Scholar 

  21. Sun Z, Liu Z, Meng J, Duan J, Xie S, Lu X, Zhu Z, Wang C, Chen S, Xu H, Yang XD (2011) Carbon nanotubes enhance cytotoxicity mediated by human lymphocytes in vitro. PLoS ONE 6:e21073. doi:10.1371/journal.pone.0021073

    Article  PubMed  CAS  Google Scholar 

  22. Vyjayanti VN, Swain U, Rao KS (2012) Age-related decline in DNA polymerase beta activity in rat brain and tissues. Neurochem Res. doi:10.1007/s11064-011-0694-9

    PubMed  Google Scholar 

  23. Sprott RL (2010) Biomarkers of aging and disease: introduction and definitions. Exp Gerontol 45:2–4. doi:10.1016/j.exger.2009.07.008

    Article  PubMed  CAS  Google Scholar 

  24. Chayot R, Danckaert A, Montagne B, Ricchetti M (2010) Lack of DNA polymerase mu affects the kinetics of DNA double-strand break repair and impacts on cellular senescence. DNA Repair (Amst) 9:1187–1199. doi:10.1016/j.dnarep.2010.09.001

    Article  CAS  Google Scholar 

  25. Albertella MR, Lau A, O’Connor MJ (2005) The overexpression of specialized DNA polymerases in cancer. DNA Repair (Amst) 4:583–593. doi:10.1016/j.dnarep.2005.01.005

    Article  CAS  Google Scholar 

  26. Sigurdson AJ, Hauptmann M, Chatterjee N, Alexander BH, Doody MM, Rutter JL, Struewing JP (2004) Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes. BMC Cancer 4:9. doi:10.1186/1471-2407-4-9

    Article  PubMed  Google Scholar 

  27. Weber F, Shen L, Fukino K, Patocs A, Mutter GL, Caldes T, Eng C (2006) Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am J Hum Genet 78:961–972. doi:10.1086/504090

    Article  PubMed  CAS  Google Scholar 

  28. Venkatesan RN, Treuting PM, Fuller ED, Goldsby RE, Norwood TH, Gooley TA, Ladiges WC, Preston BD, Loeb LA (2007) Mutation at the polymerase active site of mouse DNA polymerase delta increases genomic instability and accelerates tumorigenesis. Mol Cell Biol 27:7669–7682. doi:10.1128/MCB.00002-07

    Article  PubMed  CAS  Google Scholar 

  29. Goldsby RE, Hays LE, Chen X, Olmsted EA, Slayton WB, Spangrude GJ, Preston BD (2002) High incidence of epithelial cancers in mice deficient for DNA polymerase delta proofreading. Proc Natl Acad Sci USA 99:15560–15565. doi:10.1073/pnas.232340999

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the grands from National Nature Science Foundation of China (No. 81271924 and No. 30672469) and Beijing Nature Science Foundation (No. 7062030).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pei-Chang Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, JL., Guo, HL., Wang, PC. et al. Age-dependent down-regulation of DNA polymerase δ1 in human lymphocytes. Mol Cell Biochem 371, 157–163 (2012). https://doi.org/10.1007/s11010-012-1432-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-012-1432-6

Keywords

Navigation