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Role of the Molecular Chaperones Hsp70 and Hsp90 in the DNA Damage Response

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Heat Shock Proteins in Signaling Pathways

Part of the book series: Heat Shock Proteins ((HESP,volume 17))

Abstract

Heat Shock Protein 70 (Hsp70) and Heat Shock Protein 90 (Hsp90) are well-conserved, highly expressed molecular chaperone proteins, which assist in the folding and stabilization of the human proteome. It is not surprising that chaperones regulate and fine-tune many important signal transduction pathways. An important example of this is the DNA Damage Response Pathway (DDR), which is critical for DNA repair after creation of single or double strand breaks. An increasing body of work suggests that many DDR proteins are kept active by Hsp70 and Hsp90 proteins. Detailed understanding of these interactions may lead to the development of novel anti-cancer therapies.

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Abbreviations

AP:

apurinic

ATM:

ataxia-telangiectasia-mutated kinase

BER:

Base Excision Repair

DDR:

DNA damage response

DSB:

double strand break

HR:

homologous recombination pathway

HS:

Heat Shock

HSF:

Heat Shock Factor

Hsp:

Heat Shock Protein

HU:

Hydroxyurea

IR:

Ionizing Radiation

MRN:

MRE11–RAD50–NBS1 complex

MRX:

Mre11p–Rad50p–Xrs2p

NBD:

Nucleotide-binding domain

NER:

Nucleotide Excision repair

NHEJ:

non-homologous end joining pathway

MMR:

Mismatch repair pathway

MMS:

methylmethanesulphonate

SBD:

Substrate-binding domain

References

  • Arlander SJ, Eapen AK, Vroman BT, McDonald RJ, Toft DO, Karnitz LM (2003) Hsp90 inhibition depletes Chk1 and sensitizes tumor cells to replication stress. J Biol Chem 278:52572–52577

    Article  CAS  Google Scholar 

  • Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506

    Article  CAS  Google Scholar 

  • Blackford AN, Jackson SP (2017) ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell 66:801–817

    Article  CAS  Google Scholar 

  • Boulianne B, Feldhahn N (2017) Transcribing malignancy: transcription-associated genomic instability in cancer. Oncogene 37:971–981

    Article  Google Scholar 

  • Boulton SJ, Jackson SP (1998) Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. EMBO J 17:1819–1828

    Article  CAS  Google Scholar 

  • Bronner CE, Baker SM, Morrison PT et al (1994) Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368:258–261

    Article  CAS  Google Scholar 

  • Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276:42462–42467

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Cheng AN, Fan CC, Lo YK et al (2017) Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ATM signaling that overcomes replication stress in cancer. Sci Rep 7:17024

    Article  Google Scholar 

  • Chiruvella KK, Liang Z, Wilson TE (2013) Repair of double-strand breaks by end joining. Cold Spring Harb Perspect Biol 5:a012757

    Article  Google Scholar 

  • de Laat WL, Jaspers NG, Hoeijmakers JH (1999) Molecular mechanism of nucleotide excision repair. Genes Dev 13:768–785

    Article  Google Scholar 

  • Dote H, Burgan WE, Camphausen K, Tofilon PJ (2006) Inhibition of hsp90 compromises the DNA damage response to radiation. Cancer Res 66:9211–9220

    Article  CAS  Google Scholar 

  • Fell VL, Schild-Poulter C (2012) Ku regulates signaling to DNA damage response pathways through the Ku70 von Willebrand A domain. Mol Cell Biol 32:76–87

    Article  CAS  Google Scholar 

  • Hakem R (2008) DNA-damage repair; the good, the bad, and the ugly. EMBO J 27:589–605

    Article  CAS  Google Scholar 

  • Halliwell B, Aruoma OI (1991) DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS Lett 281:9–19

    Article  CAS  Google Scholar 

  • Houtgraaf JH, Versmissen J, van der Giessen WJ (2006) A concise review of DNA damage checkpoints and repair in mammalian cells. Cardiovasc Revasc Med 7:165–172

    Article  Google Scholar 

  • Hunter KJ, Deen DF, Marton LJ (1989) Differential response to 1,3-bis (2-chloroethyl)-1-nitrosourea in drug-resistant and -sensitive 9L rat brain tumor cells pretreated with alpha-difluoromethylornithine and 6-thioguanine. Int J Cancer 44:658–660

    Article  CAS  Google Scholar 

  • Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461:1071–1078

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Ko JC, Chen HJ, Huang YC et al (2012) HSP90 inhibition induces cytotoxicity via down-regulation of Rad51 expression and DNA repair capacity in non-small cell lung cancer cells. Regul Toxicol Pharmacol 64:415–424

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Li QQ, Hao JJ, Zhang Z et al (2017) Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics. Sci Rep 7:201

    Article  Google Scholar 

  • Lieber MR (2010) The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79:181–211

    Article  CAS  Google Scholar 

  • Martin LJ (2008) DNA damage and repair: relevance to mechanisms of neurodegeneration. J Neuropathol Exp Neurol 67:377–387

    Article  CAS  Google Scholar 

  • McGowan CH, Russell P (2004) The DNA damage response: sensing and signaling. Curr Opin Cell Biol 16:629–633

    Article  CAS  Google Scholar 

  • McKinnon PJ (2012) ATM and the molecular pathogenesis of ataxia telangiectasia. Annu Rev Pathol 7:303–321

    Article  CAS  Google Scholar 

  • Moore JK, Haber JE (1996) Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae. Mol Cell Biol 16:2164–2173

    Article  CAS  Google Scholar 

  • Nitika, Truman AW (2017) Cracking the chaperone code: cellular roles for Hsp70 phosphorylation. Trends Biochem Sci 42:932–935

    Article  CAS  Google Scholar 

  • Niu P, Liu L, Gong Z et al (2006) Overexpressed heat shock protein 70 protects cells against DNA damage caused by ultraviolet C in a dose-dependent manner. Cell Stress Chaperones 11:162–169

    Article  CAS  Google Scholar 

  • Noguchi M, Yu D, Hirayama R et al (2006) Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Biochem Biophys Res Commun 351:658–663

    Article  CAS  Google Scholar 

  • Peng G, Lin SY (2011) Exploiting the homologous recombination DNA repair network for targeted cancer therapy. World J Clin Oncol 2:73–79

    Article  Google Scholar 

  • Pennisi R, Ascenzi P, di Masi A (2015) Hsp90: a new player in DNA repair? Biomol Ther 5:2589–2618

    CAS  Google Scholar 

  • Pennisi R, Antoccia A, Leone S, Ascenzi P, di Masi A (2017) Hsp90alpha regulates ATM and NBN functions in sensing and repair of DNA double-strand breaks. FEBS J 284:2378–2395

    Article  CAS  Google Scholar 

  • Pfuhler S, Wolf HU (1996) Detection of DNA-crosslinking agents with the alkaline comet assay. Environ Mol Mutagen 27:196–201

    Article  CAS  Google Scholar 

  • Quanz M, Herbette A, Sayarath M et al (2012) Heat shock protein 90alpha (Hsp90alpha) is phosphorylated in response to DNA damage and accumulates in repair foci. J Biol Chem 287:8803–8815

    Article  CAS  Google Scholar 

  • Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39–85

    Article  CAS  Google Scholar 

  • Santivasi WL, Xia F (2014) Ionizing radiation-induced DNA damage, response, and repair. Antioxid Redox Signal 21:251–259

    Article  CAS  Google Scholar 

  • Sherman MY, Gabai V, O’Callaghan C, Yaglom J (2007) Molecular chaperones regulate p53 and suppress senescence programs. FEBS Lett 581:3711–3715

    Article  CAS  Google Scholar 

  • Shiloh Y, Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14:197–210

    Article  CAS  Google Scholar 

  • Sluder IT, Nitika, Knighton LE, Truman AW (2018) The Hsp70 co-chaperone Ydj1/HDJ2 regulates ribonucleotide reductase activity. PLoS Genet 14(11):e1007462

    Article  Google Scholar 

  • Stecklein SR, Kumaraswamy E, Behbod F et al (2012) BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation. Proc Natl Acad Sci U S A 109:13650–13655

    Article  CAS  Google Scholar 

  • Truman AW, Kristjansdottir K, Wolfgeher D et al (2015) Quantitative proteomics of the yeast Hsp70/Hsp90 interactomes during DNA damage reveal chaperone-dependent regulation of ribonucleotide reductase. J Proteome 112:285–300

    Article  CAS  Google Scholar 

  • Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y (2003) Requirement of the MRN complex for ATM activation by DNA damage. EMBO J 22:5612–5621

    Article  CAS  Google Scholar 

  • van den Bosch M, Bree RT, Lowndes NF (2003) The MRN complex: coordinating and mediating the response to broken chromosomes. EMBO Rep 4:844–849

    Article  Google Scholar 

  • Woodford MR, Dunn D, Miller JB, Jamal S, Neckers L, Mollapour M (2016) Impact of posttranslational modifications on the anticancer activity of Hsp90 inhibitors. Adv Cancer Res 129:31–50

    Article  CAS  Google Scholar 

  • Zhang X, Succi J, Feng Z, Prithivirajsingh S, Story MD, Legerski RJ (2004) Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response. Mol Cell Biol 24:9207–9220

    Article  CAS  Google Scholar 

  • Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439

    Article  CAS  Google Scholar 

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Acknowledgments

This project was supported by NCIR15CA208773.

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Authors and Affiliations

  1. Department of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC, USA

    Laura E. Knighton & Andrew W. Truman

Authors
  1. Laura E. Knighton
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  2. Andrew W. Truman
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Correspondence to Andrew W. Truman .

Editor information

Editors and Affiliations

  1. Professor, Department of Medicine and Director, Precision Therapeutics Proteogenomics Diagnostic Center Eleanor N. Dana Cancer Center, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Punit Kaur

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Knighton, L.E., Truman, A.W. (2019). Role of the Molecular Chaperones Hsp70 and Hsp90 in the DNA Damage Response. In: Asea, A., Kaur, P. (eds) Heat Shock Proteins in Signaling Pathways. Heat Shock Proteins, vol 17. Springer, Cham. https://doi.org/10.1007/978-3-030-03952-3_18

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