Skip to main content

Advertisement

SpringerLink
Log in

Endocrine disrupting chemicals may deregulate DNA repair through estrogen receptor mediated seizing of CBP/p300 acetylase

  • Short Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

Environmental pollutants are known to induce DNA breaks, leading to genomic instability. Here, we propose a novel mechanism for the genotoxic effects exerted by environmentally exposed endocrine-disrupting chemicals (EDCs).

Methods

Bibliographic research and presentation of the analysis.

Discussion

In mammals, nucleotide excision repair, base excision repair, homologous recombination and non-homologous end-joining pathways are some of the major DNA repair pathways. p300 along with CREB-binding protein (CBP) contributes to chromatin remodeling, DNA damage response and repair of both single- and double-stranded DNA breaks. In addition to its role in DNA repair, CBP/p300 also acts as a coactivator to interact with the estrogen receptor and androgen receptor during its estrogen- and androgen-dependent transactivation, respectively. Since activated estrogen receptors (ERs) seize p300 from the repressed genes and redistribute it to the enhancer genes to activate transcription, the cellular functioning may be based on a balance between these pathways and any disturbance in one may alter the other, leading to undesirable physiological effects.

Conclusion

In conclusion, CBP/p300 is important for DNA repair and nuclear hormone receptor transactivation. Activated hormone receptors can sequester p300 to regulate the hormonal effects. Hence, we believe that activation of ERs by EDCs results in sequestration of CBP/p300 for ER transactivation and transcription initiation of its target genes, leading to a competition for CBP/P300, resulting in the deregulation of all other pathways involving p300/CBP.

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.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Damstra T, Barlow S, Bergman A, Kavlock R et al (2002) Global assessment of the state-of-the-science of endocrine disruptors. World Health Organization, Geneva, pp 11–32

    Google Scholar 

  2. De Coster S, van Larebeke N (2012) Endocrine-disrupting chemicals: associated disorders and mechanisms of action. J Environ Public Health 2012:713696

    PubMed  PubMed Central  Google Scholar 

  3. Foresta C, Tescari S, Di Nisio A (2018) Impact of perfluorochemicals on human health and reproduction: a male's perspective. J Endocrinol Invest 41:639–645

    CAS  PubMed  Google Scholar 

  4. Bergman Å, Heindel JJ, Jobling S, Kidd K et al (2013) State of the science of endocrine disrupting chemicals 2012. World Health Organization, Geneva

    Google Scholar 

  5. Al-Saleh I, Al-Rajudi T, Al-Qudaihi G, Manogaran P (2017) Evaluating the potential genotoxicity of phthalates esters (PAEs) in perfumes using in vitro assays. Environ Sci Pollut Res Int 24:23903–23914

    CAS  PubMed  Google Scholar 

  6. Ding ZM, Jiao XF, Wu D, Zhang JY et al (2017) Bisphenol AF negatively affects oocyte maturation of mouse in vitro through increasing oxidative stress and DNA damage. Chem Biol Interact 278:222–229

    CAS  PubMed  Google Scholar 

  7. Ferreira LL, Couto R, Oliveira PJ (2015) Bisphenol A as epigenetic modulator: setting the stage for carcinogenesis? Eur J Clin Invest 45(Suppl 1):32–36

    CAS  PubMed  Google Scholar 

  8. Prusinski Fernung LE, Yang Q, Sakamuro D, Kumari A et al (2018) Endocrine disruptor exposure during development increases incidence of uterine fibroids by altering DNA repair in myometrial stem cells. Biol Reprod 99:735–748

    PubMed  PubMed Central  Google Scholar 

  9. Li X, Yin P, Zhao L (2017) Effects of individual and combined toxicity of bisphenol A, dibutyl phthalate and cadmium on oxidative stress and genotoxicity in HepG 2 cells. Food Chem Toxicol 105:73–81

    CAS  PubMed  Google Scholar 

  10. Maria VL, Correia AC, Santos MA (2003) Genotoxic and hepatic biotransformation responses induced by the overflow of pulp mill and secondary-treated effluents on Anguilla anguilla L. Ecotoxicol Environ Saf 55:126–137

    CAS  PubMed  Google Scholar 

  11. Martinez-Paz P, Morales M, Martinez-Guitarte JL, Morcillo G (2013) Genotoxic effects of environmental endocrine disruptors on the aquatic insect Chironomus riparius evaluated using the comet assay. Mutat Res 758:41–47

    CAS  PubMed  Google Scholar 

  12. Morales M, Martinez-Paz P, Ozaez I, Martinez-Guitarte JL et al (2013) DNA damage and transcriptional changes induced by tributyltin (TBT) after short in vivo exposures of Chironomus riparius (Diptera) larvae. Comp Biochem Physiol C Toxicol Pharmacol 158:57–63

    CAS  PubMed  Google Scholar 

  13. Izzotti A, Kanitz S, D'Agostini F, Camoirano A et al (2009) Formation of adducts by bisphenol A, an endocrine disruptor, in DNA in vitro and in liver and mammary tissue of mice. Mutat Res 679:28–32

    CAS  PubMed  Google Scholar 

  14. Santovito A, Cannarsa E, Schleicherova D, Cervella P (2018) Clastogenic effects of bisphenol A on human cultured lymphocytes. Hum Exp Toxicol 37:69–77

    CAS  PubMed  Google Scholar 

  15. Iso T, Watanabe T, Iwamoto T, Shimamoto A et al (2006) DNA damage caused by bisphenol A and estradiol through estrogenic activity. Biol Pharm Bull 29:206–210

    CAS  PubMed  Google Scholar 

  16. Fittipaldi S, Bimonte VM, Soricelli A, Aversa A et al (2019) Cadmium exposure alters steroid receptors and proinflammatory cytokine levels in endothelial cells in vitro: a potential mechanism of endocrine disruptor atherogenic effect. J Endocrinol Invest 42:727–739

    CAS  PubMed  Google Scholar 

  17. Skipper A, Sims JN, Yedjou CG, Tchounwou PB (2016) Cadmium chloride induces DNA damage and apoptosis of human liver carcinoma cells via oxidative stress. Int J Environ Res Public Health 13:20

    Google Scholar 

  18. Guo X, Yang C, Qian X, Lei T et al (2013) Estrogen receptor alpha regulates ATM expression through miRNAs in breast cancer. Clin cancer Res 19:4994–5002

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Pedram A, Razandi M, Evinger AJ, Lee E et al (2009) Estrogen inhibits ATR signaling to cell cycle checkpoints and DNA repair. Mol Biol Cell 20:3374–3389

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Song L, Lin C, Wu Z, Gong H et al (2011) miR-18a impairs DNA damage response through downregulation of ataxia telangiectasia mutated (ATM) kinase. PLoS ONE 6:e25454

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen ST, Lin CC, Liu YS, Lin C et al (2013) Airborne particulate collected from central Taiwan induces DNA strand breaks, Poly(ADP-ribose) polymerase-1 activation, and estrogen-disrupting activity in human breast carcinoma cell lines. J Environ Sci Health A Tox Hazard Subst Environ Eng 48:173–181

    CAS  PubMed  Google Scholar 

  22. Rebbeck TR (2000) Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 18:100S–S103

    CAS  PubMed  Google Scholar 

  23. He X, Jing Y, Wang J, Li K et al (2015) Significant accumulation of persistent organic pollutants and dysregulation in multiple DNA damage repair pathways in the electronic-waste-exposed populations. Environ Res 137:458–466

    CAS  PubMed  Google Scholar 

  24. Jasso-Pineda Y, Diaz-Barriga F, Calderon J, Yanez L et al (2012) DNA damage and decreased DNA repair in peripheral blood mononuclear cells in individuals exposed to arsenic and lead in a mining site. Biol Trace Elem Res 146:141–149

    CAS  PubMed  Google Scholar 

  25. De Flora S, Micale RT, La Maestra S, Izzotti A et al (2011) Upregulation of clusterin in prostate and DNA damage in spermatozoa from bisphenol A-treated rats and formation of DNA adducts in cultured human prostatic cells. Toxicol Sci 122:45–51

    PubMed  Google Scholar 

  26. Dobrzynska MM, Radzikowska J (2013) Genotoxicity and reproductive toxicity of bisphenol A and X-ray/bisphenol A combination in male mice. Drug Chem Toxicol 36:19–26

    CAS  PubMed  Google Scholar 

  27. Xin L, Wang J, Guo S, Wu Y et al (2014) Organic extracts of coke oven emissions can induce genetic damage in metabolically competent HepG2 cells. Environ Toxicol Pharmacol 37:946–953

    CAS  PubMed  Google Scholar 

  28. Prasanth GK, Divya LM, Sadasivan C (2013) Bisphenol-A can inhibit the enzymatic activity of human superoxide dismutase. Hum Ecol Risk Assess 20:268–77

    Google Scholar 

  29. Nambiar M, Raghavan SC (2011) How does DNA break during chromosomal translocations? Nucleic Acids Res 39:5813–5825

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhu C, Mills KD, Ferguson DO, Lee C et al (2002) Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109:811–821

    CAS  PubMed  Google Scholar 

  31. Caldecott KW (2008) Single-strand break repair and genetic disease. Nat Rev Genet 9:619–631

    CAS  PubMed  Google Scholar 

  32. Krokan HE, Bjoras M (2013) Base excision repair. Cold Spring Harb Perspect Biol 5:a012583

    PubMed  PubMed Central  Google Scholar 

  33. Scharer OD (2013) Nucleotide excision repair in eukaryotes. Cold Spring Harb Perspect Biol 5:a012609

    PubMed  PubMed Central  Google Scholar 

  34. Dianov GL, Parsons JL (2007) Co-ordination of DNA single strand break repair. DNA Repair (Amst) 6:454–460

    CAS  Google Scholar 

  35. Chen J, Ghorai MK, Kenney G, Stubbe J (2008) Mechanistic studies on bleomycin-mediated DNA damage: multiple binding modes can result in double-stranded DNA cleavage. Nucleic Acids Res 36:3781–3790

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kryston TB, Georgiev AB, Pissis P, Georgakilas AG (2011) Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res 711:193–201

    CAS  PubMed  Google Scholar 

  37. Nishana M, Raghavan SC (2012) Role of recombination activating genes in the generation of antigen receptor diversity and beyond. Immunology 137:271–281

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Escargueil AE, Soares DG, Salvador M, Larsen AK et al (2008) What histone code for DNA repair? Mutat Res 658:259–270

    CAS  PubMed  Google Scholar 

  39. Iizuka M, Smith MM (2003) Functional consequences of histone modifications. Curr Opin Genet Dev 13:154–160

    CAS  PubMed  Google Scholar 

  40. Osley MA, Shen X (2006) Altering nucleosomes during DNA double-strand break repair in yeast. Trends Genet 22:671–677

    CAS  PubMed  Google Scholar 

  41. Foulds CE, Feng Q, Ding C, Bailey S et al (2013) Proteomic analysis of coregulators bound to ERalpha on DNA and nucleosomes reveals coregulator dynamics. Mol Cell 51:185–199

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Vempati RK, Jayani RS, Notani D, Sengupta A et al (2010) p300-mediated acetylation of histone H3 lysine 56 functions in DNA damage response in mammals. J Biol Chem 285:28553–28564

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Jang ER, Choi JD, Lee JS (2011) Acetyltransferase p300 regulates NBS1-mediated DNA damage response. FEBS Lett 585:47–52

    CAS  PubMed  Google Scholar 

  44. Jain S, Wei J, Mitrani LR, Bishopric NH (2012) Auto-acetylation stabilizes p300 in cardiac myocytes during acute oxidative stress, promoting STAT3 accumulation and cell survival. Breast Cancer Res Treat 135:103–114

    CAS  PubMed  Google Scholar 

  45. Ogiwara H, Ui A, Otsuka A, Satoh H et al (2011) Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors. Oncogene 30:2135–2146

    CAS  PubMed  Google Scholar 

  46. Ogiwara H, Kohno T (2012) CBP and p300 histone acetyltransferases contribute to homologous recombination by transcriptionally activating the BRCA1 and RAD51 genes. PLoS ONE 7:e52810

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Qi W, Chen H, Xiao T, Wang R et al (2016) Acetyltransferase p300 collaborates with chromodomain helicase DNA-binding protein 4 (CHD4) to facilitate DNA double-strand break repair. Mutagenesis 31:193–203

    CAS  PubMed  Google Scholar 

  48. Stauffer D, Chang B, Huang J, Dunn A et al (2007) p300/CREB-binding protein interacts with ATR and is required for the DNA replication checkpoint. J Biol Chem 282:9678–9687

    CAS  PubMed  Google Scholar 

  49. Tillhon M, Cazzalini O, Nardo T, Necchi D et al (2012) p300/CBP acetyl transferases interact with and acetylate the nucleotide excision repair factor XPG. DNA Repair (Amst) 11:844–852

    CAS  Google Scholar 

  50. Cazzalini O, Sommatis S, Tillhon M, Dutto I et al (2014) CBP and p300 acetylate PCNA to link its degradation with nucleotide excision repair synthesis. Nucleic Acids Res 42:8433–8448

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Hasan S, Hassa PO, Imhof R, Hottiger MO (2001) Transcription coactivator p300 binds PCNA and may have a role in DNA repair synthesis. Nature 410:387–391

    CAS  PubMed  Google Scholar 

  52. Wang QE, Han C, Zhao R, Wani G et al (2013) p38 MAPK- and Akt-mediated p300 phosphorylation regulates its degradation to facilitate nucleotide excision repair. Nucleic Acids Res 41:1722–1733

    CAS  PubMed  Google Scholar 

  53. Hasan S, El-Andaloussi N, Hardeland U, Hassa PO et al (2002) Acetylation regulates the DNA end-trimming activity of DNA polymerase beta. Mol Cell 10:1213–1222

    CAS  PubMed  Google Scholar 

  54. Hasan S, Stucki M, Hassa PO, Imhof R et al (2001) Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300. Mol Cell 7:1221–1231

    CAS  PubMed  Google Scholar 

  55. Bhakat KK, Mokkapati SK, Boldogh I, Hazra TK et al (2006) Acetylation of human 8-oxoguanine-DNA glycosylase by p300 and its role in 8-oxoguanine repair in vivo. Mol Cell Biol 26:1654–1665

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Dutta A, Yang C, Sengupta S, Mitra S et al (2015) New paradigms in the repair of oxidative damage in human genome: mechanisms ensuring repair of mutagenic base lesions during replication and involvement of accessory proteins. Cell Mol Life Sci 72:1679–1698

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Tini M, Benecke A, Um SJ, Torchia J et al (2002) Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription. Mol Cell 9:265–277

    CAS  PubMed  Google Scholar 

  58. Likhite VS, Cass EI, Anderson SD, Yates JR et al (2004) Interaction of estrogen receptor alpha with 3-methyladenine DNA glycosylase modulates transcription and DNA repair. J Biol Chem 279:16875–16882

    CAS  PubMed  Google Scholar 

  59. Bannister AJ, Kouzarides T (1996) The CBP co-activator is a histone acetyltransferase. Nature 384:641–643

    CAS  PubMed  Google Scholar 

  60. Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90:595–606

    CAS  PubMed  Google Scholar 

  61. Kraus WL, Manning ET, Kadonaga JT (1999) Biochemical analysis of distinct activation functions in p300 that enhance transcription initiation with chromatin templates. Mol Cell Biol 19:8123–8135

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Munshi N, Merika M, Yie J, Senger K et al (1998) Acetylation of HMG I(Y) by CBP turns off IFN beta expression by disrupting the enhanceosome. Mol Cell 2:457–467

    CAS  PubMed  Google Scholar 

  63. Ogryzko VV, Schiltz RL, Russanova V, Howard BH et al (1996) The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87:953–959

    CAS  PubMed  Google Scholar 

  64. Polesskaya A, Duquet A, Naguibneva I, Weise C et al (2000) CREB-binding protein/p300 activates MyoD by acetylation. J Biol Chem 275:34359–34364

    CAS  PubMed  Google Scholar 

  65. Shankaranarayanan P, Chaitidis P, Kuhn H, Nigam S (2001) Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene. J Biol Chem 276:42753–42760

    CAS  PubMed  Google Scholar 

  66. Boyes J, Byfield P, Nakatani Y, Ogryzko V (1998) Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 396:594–598

    CAS  PubMed  Google Scholar 

  67. Imhof A, Yang XJ, Ogryzko VV, Nakatani Y et al (1997) Acetylation of general transcription factors by histone acetyltransferases. Curr Biol 7:689–692

    CAS  PubMed  Google Scholar 

  68. Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3:950–964

    CAS  PubMed  Google Scholar 

  69. Rastinejad F, Huang P, Chandra V, Khorasanizadeh S (2013) Understanding nuclear receptor form and function using structural biology. J Mol Endocrinol 51:T1–T21

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Safe S (2001) Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-p1 interactions. Vitam Horm 62:231–252

    CAS  PubMed  Google Scholar 

  71. Marino M, Galluzzo P, Ascenzi P (2006) Estrogen signaling multiple pathways to impact gene transcription. Curr Genom 7:497–508

    CAS  Google Scholar 

  72. Sheppard HM, Harries JC, Hussain S, Bevan C et al (2001) Analysis of the steroid receptor coactivator 1 (SRC1)-CREB binding protein interaction interface and its importance for the function of SRC1. Mol Cell Biol 21:39–50

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Wong CW, Komm B, Cheskis BJ (2001) Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands. Biochemistry 40:6756–6765

    CAS  PubMed  Google Scholar 

  74. Demarest SJ, Martinez-Yamout M, Chung J, Chen H et al (2002) Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 415:549–553

    CAS  PubMed  Google Scholar 

  75. Stossi F, Madak-Erdogan Z, Katzenellenbogen BS (2009) Estrogen receptor alpha represses transcription of early target genes via p300 and CtBP1. Mol Cell Biol 29:1749–1759

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Guertin MJ, Zhang X, Coonrod SA, Hager GL (2014) Transient estrogen receptor binding and p300 redistribution support a squelching mechanism for estradiol-repressed genes. Mol Endocrinol 28:1522–1533

    PubMed  PubMed Central  Google Scholar 

  77. Murakami S, Nagari A, Kraus WL (2017) Dynamic assembly and activation of estrogen receptor alpha enhancers through coregulator switching. Genes Dev 31:1535–1548

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

DLM is supported by Start-up Grant (YSS/2015/000987) from DST, Government of India.

Author information

Authors and Affiliations

  1. Molecular Biology Division, Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, 575018, India

    M. D. Lakshmanan & K. Shaheer

Authors
  1. M. D. Lakshmanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Shaheer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. D. Lakshmanan.

Ethics declarations

Conflict of interest

The authors hereby declare that they have no actual or potential competing/financial interest.

Ethical approval

This article doesn't involve any human subjects or animal work.

Informed consent

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 551 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lakshmanan, M.D., Shaheer, K. Endocrine disrupting chemicals may deregulate DNA repair through estrogen receptor mediated seizing of CBP/p300 acetylase. J Endocrinol Invest 43, 1189–1196 (2020). https://doi.org/10.1007/s40618-020-01241-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-020-01241-5

Keywords

Search

Navigation