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ATM and ATR Activation Through Crosstalk Between DNA Damage Response Pathways

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Abstract

Cells losing the ability to self-regulate in response to damage are a hallmark of cancer. When a cell encounters damage, regulatory pathways estimate the severity of damage and promote repair, cell cycle arrest, or apoptosis. This decision-making process would be remarkable if it were based on the total amount of damage in the cell, but because damage detection pathways vary in the rate and intensity with which they promote pro-apoptotic factors, the cell’s real challenge is to reconcile dissimilar signals. Crosstalk between repair pathways, crosstalk between pro-apoptotic signaling kinases, and signals induced by damage by-products complicate the process further. The cell’s response to \(\gamma \) and UV radiation neatly illustrates this concept. While these forms of radiation produce lesions associated with two different pro-apoptotic signaling kinases, ATM and ATR, recent experiments show that ATM and ATR react to both forms of radiation. To simulate the pro-apoptotic signal induced by \(\gamma \) and UV radiation, we construct a mathematical model that includes three modes of crosstalk between ATM and ATR signaling pathways: positive feedback between ATM/ATR and repair proteins, ATM and ATR mutual upregulation, and changes in lesion topology induced by replication stress or repair. We calibrate the model to agree with 21 experimental claims about ATM and ATR crosstalk. We alter the model by adding or removing specific processes and then examine the effects of each process on ATM/ATR crosstalk by recording which claims the altered model violates. Not only is this the first mathematical model of ATM/ATR crosstalk, it provides a strong argument for treating pro-apoptotic signaling as a holistic effort rather than attributing it to a single dominant kinase.

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Code Availability

The code used in this paper is available on GitHub at https://github.com/lfedak/atmandatr.

References

  • Adamowicz M (2018) Breaking up with ATM. J Immunol Sci 2(1):26

    Article  Google Scholar 

  • Adimoolam S, Ford JM (2003) p53 and regulation of DNA damage recognition during nucleotide excision repair. DNA Repair 2(9):947–954

    Article  Google Scholar 

  • Auclair Y, Rouget R, Drobetsky EA (2009) ATR kinase as master regulator of nucleotide excision repair during S phase of the cell cycle. Cell Cycle 8(12):1865–1871

    Article  Google Scholar 

  • Awasthi P, Foiani M, Kumar A (2015) ATM and ATR signaling at a glance. J Cell Sci 128(23):4255–4262

    Google Scholar 

  • Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421(6922):499–506

    Article  Google Scholar 

  • Bartek J, Lukas C, Lukas J (2004) Checking on DNA damage in S phase. Nat Rev Mol Cell Biol 5(10):792

    Article  Google Scholar 

  • Batchelor E, Mock CS, Bhan I, Loewer A, Lahav G (2008) Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage. Mol Cell 30(3):277–289

    Article  Google Scholar 

  • Batchelor E, Loewer A, Mock C, Lahav G (2011) Stimulus-dependent dynamics of p53 in single cells. Mol Syst Biol 7(1):488

    Article  Google Scholar 

  • Buisson R, Boisvert JL, Benes CH, Zou L (2015) Distinct but concerted roles of ATR, DNA-PK, and Chk1 in countering replication stress during S phase. Mol Cell 59(6):1011–1024

    Article  Google Scholar 

  • Burrows AE, Elledge SJ (2008) How ATR turns on: TopBP1 goes on ATRIP with ATR. Genes Dev 22(11):1416–1421

    Article  Google Scholar 

  • Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9(8):616

    Article  Google Scholar 

  • Cliby WA, Lewis KA, Lilly KK, Kaufmann SH (2002) S phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. J Biol Chem 277(2):1599–1606

    Article  Google Scholar 

  • Cuadrado M, Martinez-Pastor B, Murga M, Toledo LI, Gutierrez-Martinez P, Lopez E, Fernandez-Capetillo O (2006) ATM regulates ATR chromatin loading in response to DNA double-strand breaks. J Exp Med 203(2):297–303

    Article  Google Scholar 

  • DiBiase SJ, Zeng ZC, Chen R, Hyslop T, Curran WJ, Iliakis G (2000) DNA-dependent protein kinase stimulates an independently active, nonhomologous, end-joining apparatus. Cancer Res 60(5):1245–1253

    Google Scholar 

  • Dupré A, Boyer-Chatenet L, Gautier J (2006) Two-step activation of ATM by DNA and the Mre11-Rad50-Nbs1 complex. Nat Struct Mol Biol 13(5):451

    Article  Google Scholar 

  • Eliaš J, Dimitrio L, Clairambault J, Natalini R (2014) The dynamics of p53 in single cells: physiologically based ODE and reaction–diffusion PDE models. Phys Biol 11(4):045001

    Article  Google Scholar 

  • Gamper AM, Rofougaran R, Watkins SC, Greenberger JS, Beumer JH, Bakkenist CJ (2013) ATR kinase activation in G1 phase facilitates the repair of ionizing radiation-induced DNA damage. Nucl Acids Res 41(22):10334–10344

    Article  Google Scholar 

  • Gannon HS, Woda BA, Jones SN (2012) ATM phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice. Cancer Cell 21(5):668–679

    Article  Google Scholar 

  • Hannan MA, Hellani A, Al-Khodairy FM, Kunhi M, Siddiqui Y, Al-Yussef N, Pangue-Cruz N, Siewertsen M, Al-Ahdal MN, Aboussekhra A (2002) Deficiency in the repair of UV-induced DNA damage in human skin fibroblasts compromised for the ATM gene. Carcinogenesis 23(10):1617–1624

    Article  Google Scholar 

  • Harper JW, Elledge SJ (2007) The DNA damage response: ten years after. Mol Cell 28(5):739–745

    Article  Google Scholar 

  • Ho B, Baryshnikova A, Brown GW (2018) Unification of protein abundance datasets yields a quantitative Saccharomyces cerevisiae proteome. Cell Syst 6(2):192–205

    Article  Google Scholar 

  • Iliakis G, Wang H, Perrault A, Boecker W, Rosidi B, Windhofer F, Wu W, Guan J, Terzoudi G, Pantelias G (2004) Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenet Genome Res 104(1–4):14–20

    Article  Google Scholar 

  • Jackson SP (2002) Sensing and repairing DNA double-strand breaks. Carcinogenesis 23(5):687–696

    Article  Google Scholar 

  • Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP (2006) ATM-and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8(1):37

    Article  Google Scholar 

  • Kodama M, Otsubo C, Hirota T, Yokota J, Enari M, Taya Y (2010) Requirement of ATM for rapid p53 phosphorylation at Ser46 without Ser/Thr-Gln sequences. Mol Cell Biol 30(7):1620–1633

    Article  Google Scholar 

  • Kousholt AN, Fugger K, Hoffmann S, Larsen BD, Menzel T, Sartori AA, Sørensen CS (2012) CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation. J Cell Biol 197(7):869–876

    Article  Google Scholar 

  • Kurz EU, Douglas P, Lees-Miller SP (2004) Doxorubicin activates ATM-dependent phosphorylation of multiple downstream targets in part through the generation of reactive oxygen species. J Biol Chem 279(51):53272–53281

    Article  Google Scholar 

  • Lavin M, Kozlov S, Gatei M, Kijas A (2015) ATM-dependent phosphorylation of all three members of the MRN complex: from sensor to adaptor. Biomolecules 5(4):2877–2902

    Article  Google Scholar 

  • Lee JH, Paull TT (2005) ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308(5721):551–554

    Article  Google Scholar 

  • Li Z, Ni M, Li J, Zhang Y, Ouyang Q, Tang C (2011) Decision making of the p53 network: death by integration. J Theor Biol 271(1):205–211

    Article  MATH  Google Scholar 

  • Liu L, Choi JH, Yim H, Choi JS, Park BD, Cho SJ, Lee SK (2009) ATR (AT mutated Rad3 related) activity stabilizes Cdc6 and delays G2/M-phase entry during hydroxyurea-induced S-phase arrest of HeLa cells. Int J Biochem Cell Biol 41(6):1410–1420

    Article  Google Scholar 

  • Loewer A, Karanam K, Mock C, Lahav G (2013) The p53 response in single cells is linearly correlated to the number of DNA breaks without a distinct threshold. BMC Biol 11(1):1

    Article  Google Scholar 

  • Ma L, Wagner J, Rice J, Hu W, Levine AJ, Stolovitzky GA (2005) A plausible model for the digital response of p53 to DNA damage. Proc Natl Acad Sci U S A 102(40):14266–14271

    Article  Google Scholar 

  • Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y et al (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316(5828):1160–1166

    Article  Google Scholar 

  • Meldrum RA, Botchway SW, Wharton CW, Hirst GJ (2003) Nanoscale spatial induction of ultraviolet photoproducts in cellular DNA by three-photon near-infrared absorption. EMBO Rep 4(12):1144–1149

    Article  Google Scholar 

  • Mladenov E, Fan X, Dueva R, Soni A, Iliakis G (2019) Radiation-dose-dependent functional synergisms between ATM, ATR and DNA-PKcs in checkpoint control and resection in G 2-phase. Sci Rep 9(1):8255

    Article  Google Scholar 

  • Mladenov E, Fan X, Paul-Konietzko K, Soni A, Iliakis G (2019) DNA-PKcs and ATM epistatically suppress DNA end resection and hyperactivation of ATR-dependent G 2-checkpoint in S-phase irradiated cells. Sci Rep 9(1):1–16

    Google Scholar 

  • Myers JS, Cortez D (2006) Rapid activation of ATR by ionizing radiation requires ATM and Mre11. J Biol Chem 281(14):9346–9350

    Article  Google Scholar 

  • Pabla N, Huang S, Mi QS, Daniel R, Dong Z (2008) ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. J Biol Chem 283(10):6572–6583

    Article  Google Scholar 

  • Ray A, Milum K, Battu A, Wani G, Wani AA (2013) NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites. DNA Repair 12(4):273–283

    Article  Google Scholar 

  • Ray A, Blevins C, Wani G, Wani AA (2016) ATR-and ATM-mediated DNA damage response is dependent on excision repair assembly during G1 but not in S phase of cell cycle. PLoS One 11(7):e0159344

    Article  Google Scholar 

  • Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB (2007) p53-deficient cells rely on ATM-and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11(2):175–189

    Article  Google Scholar 

  • Reynolds P, Anderson JA, Harper JV, Hill MA, Botchway SW, Parker AW, O’neill P (2012) The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage. Nucl Acids Res 40(21):10821–10831

    Article  Google Scholar 

  • Shechter D, Costanzo V, Gautier J (2004) Regulation of DNA replication by ATR: signaling in response to DNA intermediates. DNA Repair 3(8–9):901–908

    Article  Google Scholar 

  • Shiotani B, Zou L (2009) Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks. Mol Cell 33(5):547–558

    Article  Google Scholar 

  • Stiff T, Walker SA, Cerosaletti K, Goodarzi AA, Petermann E, Concannon P, O’Driscoll M, Jeggo PA (2006) ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO J 25(24):5775–5782

    Article  Google Scholar 

  • Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, Altman RB (2011) Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genom 21(7):440

    Article  Google Scholar 

  • Tomimatsu N, Mukherjee B, Burma S (2009) Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM-deficient cells. EMBO Rep 10(6):629–635

    Article  Google Scholar 

  • Ünsal-Kaçmaz K, Makhov AM, Griffith JD, Sancar A (2002) Preferential binding of ATR protein to UV-damaged DNA. Proc Natl Acad Sci 99(10):6673–6678

    Article  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(9):844–849

    Article  Google Scholar 

  • Vrouwe MG, Pines A, Overmeer RM, Hanada K, Mullenders LH (2011) UV-induced photolesions elicit ATR-kinase-dependent signaling in non-cycling cells through nucleotide excision repair-dependent and-independent pathways. J Cell Sci 124(3):435–446

    Article  Google Scholar 

  • Wang D, Eraslan B, Wieland T, Hallström B, Hopf T, Zolg DP, Zecha J, Asplund A, Li L, Meng C et al (2019) A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Mol Syst Biol 15(2):e8503

    Article  Google Scholar 

  • Ward JF (1988) DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. In: Progress in nucleic acid research and molecular biology, vol 35. Elsevier, pp 95–125

  • Ward J (1994) The complexity of DNA damage: relevance to biological consequences. Int J Radiat Biol 66(5):427–432

    Article  Google Scholar 

  • Ward IM, Minn K, Chen J (2004) UV-induced ataxia-telangiectasia-mutated and Rad3-related (ATR) activation requires replication stress. J Biol Chem 279(11):9677–9680

    Article  Google Scholar 

  • Weinberg R (2013) The biology of cancer. Garland Science, New York

    Book  Google Scholar 

  • Yoo HY, Kumagai A, Shevchenko A, Shevchenko A, Dunphy WG (2007) Ataxia-telangiectasia mutated (ATM)-dependent activation of ATR occurs through phosphorylation of TopBP1 by ATM. J Biol Chem 282(24):17501–17506

    Article  Google Scholar 

  • Zhang XP, Liu F, Cheng Z, Wang W (2009) Cell fate decision mediated by p53 pulses. Proc Natl Acad Sci 106(30):12245–12250

    Article  Google Scholar 

  • Zhang XP, Liu F, Wang W (2014) Interplay between Mdm2 and HIPK2 in the DNA damage response. J R Soc Interface 11(96):20140319

    Article  Google Scholar 

  • Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300(5625):1542–1548

    Article  Google Scholar 

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Funding

Elizabeth A. Fedak was supported by Research Training in Mathematical and Computational Biology Grant 1148230. Elizabeth A. Fedak and Frederick R. Adler were supported by NIH/NCI U54 Grant CA209978 to Andrea Bild. Joshua D. Schiffman and Lisa M. Abegglen are supported through the EP53 Program and its generous funding provided to Huntsman Cancer Institute by the State of Utah. Joshua D. Schiffman is also supported by Hyundai Hope on Wheels, 5 For The Fight, Kneaders Bakery & Café Hope Campaign, Soccer for Hope Foundation, and Li-Fraumeni Syndrome Association.

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Authors and Affiliations

  1. Department of Mathematics, The University of Utah, 155 Presidents Circle, Salt Lake City, UT, 84112, USA

    Elizabeth A. Fedak & Frederick R. Adler

  2. Department of Biology, The University of Utah, 257 Presidents Circle, Salt Lake City, UT, 84112, USA

    Frederick R. Adler

  3. Department of Oncological Sciences, Huntsman Cancer Institute, The University of Utah, 2000 Cir of Hope Dr, Salt Lake City, UT, 84112, USA

    Elizabeth A. Fedak, Lisa M. Abegglen & Joshua D. Schiffman

  4. Department of Pediatrics, The University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA

    Lisa M. Abegglen & Joshua D. Schiffman

  5. PEEL Therapeutics, Inc., Salt Lake City, UT, 84108, USA

    Lisa M. Abegglen & Joshua D. Schiffman

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  1. Elizabeth A. Fedak
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  2. Frederick R. Adler
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  3. Lisa M. Abegglen
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  4. Joshua D. Schiffman
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Contributions

EAF contributed to conceptualization, methodology, software, validation, formal analysis, writing—original draft, and writing—review and editing. FRA was involved in conceptualization, methodology, writing—review and editing, supervision, and funding acquisition. LMA and JDS contributed to writing—review and editing, and supervision.

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Correspondence to Elizabeth A. Fedak.

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Conflict of interest

Lisa M. Abegglen is a consultant and a stock option holder of PEEL Therapeutics, Inc. Joshua D. Schiffman is employed by and a stock option holder of PEEL Therapeutics, Inc. Elizabeth A. Fedak and Frederick R. Adler declare that they have no conflict of interest.

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Fedak, E.A., Adler, F.R., Abegglen, L.M. et al. ATM and ATR Activation Through Crosstalk Between DNA Damage Response Pathways. Bull Math Biol 83, 38 (2021). https://doi.org/10.1007/s11538-021-00868-6

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