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The role of the DFF40/CAD endonuclease in genomic stability

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Abstract

Maintenance of genomic stability in cells is primordial for cellular integrity and protection against tumor progression. Many factors such as ultraviolet light, oxidative stress, exposure to chemical reagents, particularly mutagens and radiation, can alter the integrity of the genome. Thus, human cells are equipped with many mechanisms that prevent these irreversible lesions in the genome, as DNA repair pathways, cell cycle checkpoints, and telomeric function. These mechanisms activate cellular apoptosis to maintain DNA stability. Emerging studies have proposed a new protein in the maintenance of genomic stability: the DNA fragmentation factor (DFF). The DFF40 is an endonuclease responsible of the oligonucleosomal fragmentation of the DNA during apoptosis. The lack of DFF in renal carcinoma cells induces apoptosis without oligonucleosomal fragmentation, which poses a threat to genetic information transfer between cancerous and healthy cells. In this review, we expose the link between the DFF and genomic instability as the source of disease development.

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References

  1. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26(4):239–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Compton MM (1992) A biochemical hallmark of apoptosis: internucleosomal degradation of the genome. Cancer Metastasis Rev 11(2):105–119

    Article  CAS  PubMed  Google Scholar 

  3. Saraste A, Pulkki K (2000) Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res 45(3):528–537

    Article  CAS  PubMed  Google Scholar 

  4. Nair P, Lu M, Petersen S, Ashkenazi A (2014) Apoptosis initiation through the cell-extrinsic pathway. Methods Enzymol 544:99–128. https://doi.org/10.1016/b978-0-12-417158-9.00005-4

    Article  CAS  PubMed  Google Scholar 

  5. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516. https://doi.org/10.1080/01926230701320337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dickens LS, Boyd RS, Jukes-Jones R, Hughes MA, Robinson GL, Fairall L, Schwabe JW, Cain K, Macfarlane M (2012) A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death. Mol Cell 47(2):291–305. https://doi.org/10.1016/j.molcel.2012.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14(22):5579–5588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu X, Zou H, Widlak P, Garrard W, Wang X (1999) Activation of the apoptotic endonuclease DFF40 (caspase-activated DNase or nuclease). Oligomerization and direct interaction with histone H1. J Biol Chem 274(20):13836–13840

    Article  CAS  PubMed  Google Scholar 

  9. Meylan F, Davidson TS, Kahle E, Kinder M, Acharya K, Jankovic D, Bundoc V, Hodges M, Shevach EM, Keane-Myers A, Wang EC, Siegel RM (2008) The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity 29(1):79–89. https://doi.org/10.1016/j.immuni.2008.04.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Spierings DC, de Vries EG, Vellenga E, van den Heuvel FA, Koornstra JJ, Wesseling J, Hollema H, de Jong S (2004) Tissue distribution of the death ligand TRAIL and its receptors. J Histochem Cytochem 52(6):821–831. https://doi.org/10.1369/jhc.3A6112.2004

    Article  CAS  PubMed  Google Scholar 

  11. Ashkenazi A, Dixit VM (1999) Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 11(2):255–260

    Article  CAS  PubMed  Google Scholar 

  12. Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ, Sherwood SW, Baldwin DT, Godowski PJ, Wood WI, Gurney AL, Hillan KJ, Cohen RL, Goddard AD, Botstein D, Ashkenazi A (1998) Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396(6712):699–703. https://doi.org/10.1038/25387

    Article  CAS  PubMed  Google Scholar 

  13. Ge Z, Sanders AJ, Ye L, Jiang WG (2011) Aberrant expression and function of death receptor-3 and death decoy receptor-3 in human cancer. Exp Ther Med 2(2):167–172. https://doi.org/10.3892/etm.2011.206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Safa AR (2012) c-FLIP, a master anti-apoptotic regulator. Exp Oncol 34(3):176–184

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Suzuki Y, Nakabayashi Y, Nakata K, Reed JC, Takahashi R (2001) X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and -7 in distinct modes. J Biol Chem 276(29):27058–27063. https://doi.org/10.1074/jbc.M102415200

    Article  CAS  PubMed  Google Scholar 

  16. Schuler M, Green DR (2001) Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 29(Pt 6):684–688

    Article  CAS  PubMed  Google Scholar 

  17. Chen P, Hu YF, Wang L, Xiao WF, Bao XY, Pan C, Yi HS, Chen XY, Pan MH, Lu C (2015) Mitochondrial apoptotic pathway is activated by H2O2-mediated oxidative stress in BmN-SWU1 cells from Bombyx mori Ovary. PLoS ONE 10(7):e0134694. https://doi.org/10.1371/journal.pone.0134694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Manon S, Chaudhuri B, Guerin M (1997) Release of cytochrome c and decrease of cytochrome c oxidase in Bax-expressing yeast cells, and prevention of these effects by coexpression of Bcl-xL. FEBS Lett 415(1):29–32

    Article  CAS  PubMed  Google Scholar 

  19. Li YZ, Li CJ, Pinto AV, Pardee AB (1999) Release of mitochondrial cytochrome C in both apoptosis and necrosis induced by beta-lapachone in human carcinoma cells. Mol Med 5(4):232–239

    Article  PubMed  PubMed Central  Google Scholar 

  20. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P (2004) Toxic proteins released from mitochondria in cell death. Oncogene 23(16):2861–2874. https://doi.org/10.1038/sj.onc.1207523

    Article  CAS  PubMed  Google Scholar 

  21. Hill MM, Adrain C, Duriez PJ, Creagh EM, Martin SJ (2004) Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes. EMBO J 23(10):2134–2145. https://doi.org/10.1038/sj.emboj.7600210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2(9):647–656. https://doi.org/10.1038/nrc883

    Article  CAS  PubMed  Google Scholar 

  23. Scorrano L, Korsmeyer SJ (2003) Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun 304(3):437–444

    Article  CAS  PubMed  Google Scholar 

  24. Wu CC, Bratton SB (2013) Regulation of the intrinsic apoptosis pathway by reactive oxygen species. Antioxid Redox Signal 19(6):546–558. https://doi.org/10.1089/ars.2012.4905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shamas-Din A, Brahmbhatt H, Leber B, Andrews DW (2011) BH3-only proteins: Orchestrators of apoptosis. Biochim Biophys Acta 1813(4):508–520. https://doi.org/10.1016/j.bbamcr.2010.11.024

    Article  CAS  PubMed  Google Scholar 

  26. Widlak P, Li P, Wang X, Garrard WT (2000) Cleavage preferences of the apoptotic endonuclease DFF40 (caspase-activated DNase or nuclease) on naked DNA and chromatin substrates. J Biol Chem 275(11):8226–8232

    Article  CAS  PubMed  Google Scholar 

  27. Widlak P (2000) The DFF40/CAD endonuclease and its role in apoptosis. Acta Biochim Pol 47(4):1037–1044

    Article  CAS  PubMed  Google Scholar 

  28. Woo EJ, Kim YG, Kim MS, Han WD, Shin S, Robinson H, Park SY, Oh BH (2004) Structural mechanism for inactivation and activation of CAD/DFF40 in the apoptotic pathway. Mol Cell 14(4):531–539

    Article  CAS  PubMed  Google Scholar 

  29. Meiss G, Scholz SR, Korn C, Gimadutdinow O, Pingoud A (2001) Identification of functionally relevant histidine residues in the apoptotic nuclease CAD. Nucleic Acids Res 29(19):3901–3909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Inohara N, Koseki T, Chen S, Benedict MA, Nunez G (1999) Identification of regulatory and catalytic domains in the apoptosis nuclease DFF40/CAD. J Biol Chem 274(1):270–274

    Article  CAS  PubMed  Google Scholar 

  31. Korn C, Scholz SR, Gimadutdinow O, Pingoud A, Meiss G (2002) Involvement of conserved histidine, lysine and tyrosine residues in the mechanism of DNA cleavage by the caspase-3 activated DNase CAD. Nucleic Acids Res 30(6):1325–1332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hanus J, Kalinowska-Herok M, Widlak P (2008) The major apoptotic endonuclease DFF40/CAD is a deoxyribose-specific and double-strand-specific enzyme. Apoptosis 13(3):377–382. https://doi.org/10.1007/s10495-008-0183-z

    Article  CAS  PubMed  Google Scholar 

  33. Samejima K, Earnshaw WC (1998) ICAD/DFF regulator of apoptotic nuclease is nuclear. Exp Cell Res 243(2):453–459. https://doi.org/10.1006/excr.1998.4212

    Article  CAS  PubMed  Google Scholar 

  34. Kawane K, Fukuyama H, Adachi M, Sakahira H, Copeland NG, Gilbert DJ, Jenkin NA, Nagata S (1999) Structure and promoter analysis of murine CAD and ICAD genes. Cell Death Differ 6(8):745–752. https://doi.org/10.1038/sj.cdd.4400547

    Article  CAS  PubMed  Google Scholar 

  35. Samejima K, Earnshaw WC (2000) Differential localization of ICAD-L and ICAD-S in cells due to removal of a C-terminal NLS from ICAD-L by alternative splicing. Exp Cell Res 255(2):314–320. https://doi.org/10.1006/excr.2000.4801

    Article  CAS  PubMed  Google Scholar 

  36. Sakahira H, Enari M, Nagata S (1999) Functional differences of two forms of the inhibitor of caspase-activated DNase, ICAD-L, and ICAD-S. J Biol Chem 274(22):15740–15744

    Article  CAS  PubMed  Google Scholar 

  37. McCarty JS, Toh SY, Li P (1999) Multiple domains of DFF45 bind synergistically to DFF40: roles of caspase cleavage and sequestration of activator domain of DFF40. Biochem Biophys Res Commun 264(1):181–185. https://doi.org/10.1006/bbrc.1999.1498

    Article  CAS  PubMed  Google Scholar 

  38. Zhou P, Lugovskoy AA, McCarty JS, Li P, Wagner G (2001) Solution structure of DFF40 and DFF45 N-terminal domain complex and mutual chaperone activity of DFF40 and DFF45. Proc Natl Acad Sci USA 98(11):6051–6055. https://doi.org/10.1073/pnas.111145098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kutscher D, Pingoud A, Jeltsch A, Meiss G (2012) Identification of ICAD-derived peptides capable of inhibiting caspase-activated DNase. FEBS J 279(16):2917–2928. https://doi.org/10.1111/j.1742-4658.2012.08673.x

    Article  CAS  PubMed  Google Scholar 

  40. Gu J, Dong RP, Zhang C, McLaughlin DF, Wu MX, Schlossman SF (1999) Functional interaction of DFF35 and DFF45 with caspase-activated DNA fragmentation nuclease DFF40. J Biol Chem 274(30):20759–20762

    Article  CAS  PubMed  Google Scholar 

  41. Neimanis S, Albig W, Doenecke D, Kahle J (2007) Sequence elements in both subunits of the DNA fragmentation factor are essential for its nuclear transport. J Biol Chem 282(49):35821–35830. https://doi.org/10.1074/jbc.M703110200

    Article  CAS  PubMed  Google Scholar 

  42. Li X, Wang J, Manley JL (2005) Loss of splicing factor ASF/SF2 induces G2 cell cycle arrest and apoptosis, but inhibits internucleosomal DNA fragmentation. Genes Dev 19(22):2705–2714. https://doi.org/10.1101/gad.1359305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sunatani Y, Kamdar RP, Sharma MK, Matsui T, Sakasai R, Hashimoto M, Ishigaki Y, Matsumoto Y, Iwabuchi K (2018) Caspase-mediated cleavage of X-ray repair cross-complementing group 4 promotes apoptosis by enhancing nuclear translocation of caspase-activated DNase. Exp Cell Res 362(2):450–460. https://doi.org/10.1016/j.yexcr.2017.12.009

    Article  CAS  PubMed  Google Scholar 

  44. Widlak P, Lanuszewska J, Cary RB, Garrard WT (2003) Subunit structures and stoichiometries of human DNA fragmentation factor proteins before and after induction of apoptosis. J Biol Chem 278(29):26915–26922. https://doi.org/10.1074/jbc.M303807200

    Article  CAS  PubMed  Google Scholar 

  45. Ha HJ, Park HH (2018) Crystal structure and mutation analysis revealed that DREP2 CIDE forms a filament-like structure with features differing from those of DREP4 CIDE. Sci Rep 8(1):17810. https://doi.org/10.1038/s41598-018-36253-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Choi JY, Qiao Q, Hong SH, Kim CM, Jeong JH, Kim YG, Jung YK, Wu H, Park HH (2017) CIDE domains form functionally important higher-order assemblies for DNA fragmentation. Proc Natl Acad Sci USA 114(28):7361–7366. https://doi.org/10.1073/pnas.1705949114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Samejima K, Tone S, Earnshaw WC (2001) CAD/DFF40 nuclease is dispensable for high molecular weight DNA cleavage and stage I chromatin condensation in apoptosis. J Biol Chem 276(48):45427–45432. https://doi.org/10.1074/jbc.M108844200

    Article  CAS  PubMed  Google Scholar 

  48. Iglesias-Guimarais V, Gil-Guiñon E, Sánchez-Osuna M, Casanelles E, García-Belinchón M, Comella JX, Yuste VJ (2013) Chromatin collapse during caspase-dependent apoptotic cell death requires DNA fragmentation factor, 40-kDa subunit-/caspase-activated deoxyribonuclease-mediated 3’-OH single-strand DNA breaks. J Biol Chem 288(13):9200–9215. https://doi.org/10.1074/jbc.M112.411371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Widlak P, Garrard WT (2001) Ionic and cofactor requirements for the activity of the apoptotic endonuclease DFF40/CAD. Mol Cell Biochem 218(1–2):125–130

    Article  CAS  PubMed  Google Scholar 

  50. Tsuruta T, Oh-Hashi K, Ueno Y, Kitade Y, Kiuchi K, Hirata Y (2007) RNAi knockdown of caspase-activated DNase inhibits rotenone-induced DNA fragmentation in HeLa cells. Neurochem Int 50(4):601–606. https://doi.org/10.1016/j.neuint.2006.12.002

    Article  CAS  PubMed  Google Scholar 

  51. Hanus J, Kalinowska-Herok M, Widlak P (2010) Identification of novel putative regulators of the major apoptotic nuclease DNA Fragmentation Factor. Acta Biochim Pol 57(4):521–527

    Article  CAS  PubMed  Google Scholar 

  52. Widlak P, Kalinowska M, Parseghian MH, Lu X, Hansen JC, Garrard WT (2005) The histone H1 C-terminal domain binds to the apoptotic nuclease, DNA fragmentation factor (DFF40/CAD) and stimulates DNA cleavage. Biochemistry 44(21):7871–7878. https://doi.org/10.1021/bi050100n

    Article  CAS  PubMed  Google Scholar 

  53. Kalinowska-Herok M, Widlak P (2008) High mobility group proteins stimulate DNA cleavage by apoptotic endonuclease DFF40/CAD due to HMG-box interactions with DNA. Acta Biochim Pol 55(1):21–26

    Article  CAS  PubMed  Google Scholar 

  54. Grue P, Grasser A, Sehested M, Jensen PB, Uhse A, Straub T, Ness W, Boege F (1998) Essential mitotic functions of DNA topoisomerase IIalpha are not adopted by topoisomerase IIbeta in human H69 cells. J Biol Chem 273(50):33660–33666

    Article  CAS  PubMed  Google Scholar 

  55. Beere HM, Chresta CM, Hickman JA (1996) Selective inhibition of topoisomerase II by ICRF-193 does not support a role for topoisomerase II activity in the fragmentation of chromatin during apoptosis of human leukemia cells. Mol Pharmacol 49:842–851

    CAS  PubMed  Google Scholar 

  56. Li TK, Chen AY, Yu C, Mao Y, Wang H, Liu LF (1999) Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress. Genes Dev 13(12):1553–1560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Durrieu F, Samejima K, Fortune JM, Kandels-Lewis S, Osheroff N, Earnshaw WC (2000) DNA topoisomerase IIalpha interacts with CAD nuclease and is involved in chromatin condensation during apoptotic execution. Curr Biol 10(15):923–926

    Article  CAS  PubMed  Google Scholar 

  58. Sakahira H, Enari M, Ohsawa Y, Uchiyama Y, Nagata S (1999) Apoptotic nuclear morphological change without DNA fragmentation. Curr Biol 9(10):543–546. https://doi.org/10.1016/s0960-9822(99)80240-1

    Article  CAS  PubMed  Google Scholar 

  59. McIlroy D, Sakahira H, Talanian RV, Nagata S (1999) Involvement of caspase 3-activated DNase in internucleosomal DNA cleavage induced by diverse apoptotic stimuli. Oncogene 18(31):4401–4408. https://doi.org/10.1038/sj.onc.1202868

    Article  CAS  PubMed  Google Scholar 

  60. Zhang J, Liu X, Scherer DC, van Kaer L, Wang X, Xu M (1998) Resistance to DNA fragmentation and chromatin condensation in mice lacking the DNA fragmentation factor 45. Proc Natl Acad Sci USA 95(21):12480–12485. https://doi.org/10.1073/pnas.95.21.12480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kulbay M, Johnson B, Bernier J (2019) DNA fragmentation factor 40 expression in T cells confers sensibility to tributyltin-induced apoptosis. Toxicology 426:152255. https://doi.org/10.1016/j.tox.2019.152255

    Article  CAS  PubMed  Google Scholar 

  62. Sanchez-Osuna M, Martinez-Escardo L, Granados-Colomina C, Martinez-Soler F, Pascual-Guiral S, Iglesias-Guimarais V, Velasco R, Plans G, Vidal N, Tortosa A, Barcia C, Bruna J, Yuste VJ (2016) An intrinsic DFF40/CAD endonuclease deficiency impairs oligonucleosomal DNA hydrolysis during caspase-dependent cell death: a common trait in human glioblastoma cells. Neuro Oncol 18(7):950–961. https://doi.org/10.1093/neuonc/nov315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu Z, Dawes R, Petrova S, Beverley PC, Tchilian EZ (2006) CD45 regulates apoptosis in peripheral T lymphocytes. Int Immunol 18(6):959–966. https://doi.org/10.1093/intimm/dxl032

    Article  CAS  PubMed  Google Scholar 

  64. Desharnais P, Dupéré-Minier G, Hamelin C, Devine P, Bernier J (2008) Involvement of CD45 in DNA fragmentation in apoptosis induced by mitochondrial perturbing agents. Apoptosis 13(2):197–212. https://doi.org/10.1007/s10495-007-0162-9

    Article  CAS  PubMed  Google Scholar 

  65. Konishi S, Ishiguro H, Shibata Y, Kudo J, Terashita Y, Sugiura H, Koyama H, Kimura M, Sato A, Shinoda N, Kuwabara Y, Fujii Y (2002) Decreased expression of DFF45/ICAD is correlated with a poor prognosis in patients with esophageal carcinoma. Cancer 95(12):2473–2478. https://doi.org/10.1002/cncr.10987

    Article  CAS  PubMed  Google Scholar 

  66. Errami Y, Brim H, Oumouna-Benachour K, Oumouna M, Naura AS, Kim H, Ju J, Davis CJ, Kim JG, Ashktorab H, Fallon K, Xu M, Zhang J, Del Valle L, Boulares AH (2013) ICAD deficiency in human colon cancer and predisposition to colon tumorigenesis: linkage to apoptosis resistance and genomic instability. PLoS ONE 8(2):e57871. https://doi.org/10.1371/journal.pone.0057871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rajandram R, Razack AH, Ng KL, Gobe GC (2016) Decreased expression of inhibitor of caspase-activated DNase (ICAD) in renal cell carcinoma—tissue microarray of human samples. J Kidney Cancer VHL 3(1):1–11. https://doi.org/10.15586/jkcvhl.2016.47

    Article  PubMed  PubMed Central  Google Scholar 

  68. Banas T, Pitynski K, Okon K, Czerw A (2017) DNA fragmentation factors 40 and 45 (DFF40/DFF45) and B-cell lymphoma 2 (Bcl-2) protein are underexpressed in uterine leiomyosarcomas and may predict survival. Onco Targets Ther 10:4579–4589. https://doi.org/10.2147/ott.S142979

    Article  PubMed  PubMed Central  Google Scholar 

  69. Brustmann H (2006) DNA fragmentation factor (DFF45): expression and prognostic value in serous ovarian cancer. Pathol Res Pract 202(10):713–720. https://doi.org/10.1016/j.prp.2006.06.003

    Article  CAS  PubMed  Google Scholar 

  70. Brustmann H (2007) Poly(ADP-ribose) polymerase (PARP) and DNA-fragmentation factor (DFF45): expression and correlation in normal, hyperplastic and neoplastic endometrial tissues. Pathol Res Pract 203(2):65–72. https://doi.org/10.1016/j.prp.2006.12.003

    Article  CAS  PubMed  Google Scholar 

  71. Banas T, Pitynski K, Okon K, Winiarska A (2018) Non-endometrioid and high-grade endometrioid endometrial cancers show DNA fragmentation factor 40 (DFF40) and B-cell lymphoma 2 protein (BCL2) underexpression, which predicts disease-free and overall survival, but not DNA fragmentation factor 45 (DFF45) underexpression. BMC Cancer 18(1):418. https://doi.org/10.1186/s12885-018-4333-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bagheri F, Safarian S, Eslaminejad MB, Sheibani N (2014) Stable overexpression of DNA fragmentation factor in T-47D cells: sensitization of breast cancer cells to apoptosis in response to acetazolamide and sulfabenzamide. Mol Biol Rep 41(11):7387–7394. https://doi.org/10.1007/s11033-014-3626-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bagheri F, Safarian S, Eslaminejad MB, Sheibani N (2015) Sensitization of breast cancer cells to doxorubicin via stable cell line generation and overexpression of DFF40. Biochem Cell Biol 93(6):604–610. https://doi.org/10.1139/bcb-2015-0007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Slane JM, Lee HS, Vorhees CV, Zhang J, Xu M (2000) DNA fragmentation factor 45 deficient mice exhibit enhanced spatial learning and memory compared to wild-type control mice. Brain Res 867(1–2):70–79

    Article  CAS  PubMed  Google Scholar 

  75. Slane McQuade JM, Vorhees CV, Xu M, Zhang J (2002) DNA fragmentation factor 45 knockout mice exhibit longer memory retention in the novel object recognition task compared to wild-type mice. Physiol Behav 76(2):315–320. https://doi.org/10.1016/s0031-9384(02)00716-3

    Article  PubMed  Google Scholar 

  76. Zhang J, Lee H, Agarwala A, Wen Lou D, Xu M (2001) Dna fragmentation factor 45 mutant mice exhibit resistance to kainic acid-induced neuronal cell death. Biochem Biophys Res Commun 285(5):1143–1149. https://doi.org/10.1006/bbrc.2001.5313

    Article  CAS  PubMed  Google Scholar 

  77. Andlauer TF, Scholz-Kornehl S, Tian R, Kirchner M, Babikir HA, Depner H, Loll B, Quentin C, Gupta VK, Holt MG, Dipt S, Cressy M, Wahl MC, Fiala A, Selbach M, Schwarzel M, Sigrist SJ (2014) Drep-2 is a novel synaptic protein important for learning and memory. Elife. https://doi.org/10.7554/eLife.03895

    Article  PubMed  PubMed Central  Google Scholar 

  78. Cao G, Pei W, Lan J, Stetler RA, Luo Y, Nagayama T, Graham SH, Yin XM, Simon RP, Chen J (2001) Caspase-activated DNase/DNA fragmentation factor 40 mediates apoptotic DNA fragmentation in transient cerebral ischemia and in neuronal cultures. J Neurosci 21(13):4678–4690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chen D, Stetler RA, Cao G, Pei W, O'Horo C, Yin XM, Chen J (2000) Characterization of the rat DNA fragmentation factor 35/Inhibitor of caspase-activated DNase (Short form). The endogenous inhibitor of caspase-dependent DNA fragmentation in neuronal apoptosis. J Biol Chem 275 (49):38508–38517. doi:https://doi.org/10.1074/jbc.M003906200

  80. Didenko VV, Ngo H, Minchew CL, Boudreaux DJ, Widmayer MA, Baskin DS (2002) Caspase-3-dependent and -independent apoptosis in focal brain ischemia. Mol Med 8(7):347–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yakovlev AG, Di X, Movsesyan V, Mullins PG, Wang G, Boulares H, Zhang J, Xu M, Faden AI (2001) Presence of DNA fragmentation and lack of neuroprotective effect in DFF45 knockout mice subjected to traumatic brain injury. Mol Med 7(3):205–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Iglesias-Guimarais V, Gil-Guinon E, Gabernet G, Garcia-Belinchon M, Sanchez-Osuna M, Casanelles E, Comella JX, Yuste VJ (2012) Apoptotic DNA degradation into oligonucleosomal fragments, but not apoptotic nuclear morphology, relies on a cytosolic pool of DFF40/CAD endonuclease. J Biol Chem 287(10):7766–7779. https://doi.org/10.1074/jbc.M111.290718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sanchez-Osuna M, Garcia-Belinchon M, Iglesias-Guimarais V, Gil-Guinon E, Casanelles E, Yuste VJ (2014) Caspase-activated DNase is necessary and sufficient for oligonucleosomal DNA breakdown, but not for chromatin disassembly during caspase-dependent apoptosis of LN-18 glioblastoma cells. J Biol Chem 289(27):18752–18769. https://doi.org/10.1074/jbc.M114.550020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Masuoka J, Shiraishi T, Ichinose M, Mineta T, Tabuchi K (2001) Expression of ICAD-l and ICAD-S in human brain tumor and its cleavage upon activation of apoptosis by anti-Fas antibody. Jpn J Cancer Res 92(7):806–812. https://doi.org/10.1111/j.1349-7006.2001.tb01165.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chen YZ, Soeda E, Yang HW, Takita J, Chai L, Horii A, Inazawa J, Ohki M, Hayashi Y (2001) Homozygous deletion in a neuroblastoma cell line defined by a high-density STS map spanning human chromosome band 1p36. Genes Chromosomes Cancer 31(4):326–332. https://doi.org/10.1002/gcc.1151

    Article  CAS  PubMed  Google Scholar 

  86. Yang HW, Chen YZ, Piao HY, Takita J, Soeda E, Hayashi Y (2001) DNA fragmentation factor 45 (DFF45) gene at 1p36.2 is homozygously deleted and encodes variant transcripts in neuroblastoma cell line. Neoplasia 3(2):165–169. https://doi.org/10.1038/sj.neo.7900141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Abel F, Sjoberg RM, Ejeskar K, Krona C, Martinsson T (2002) Analyses of apoptotic regulators CASP9 and DFFA at 1P36.2, reveal rare allele variants in human neuroblastoma tumours. Br J Cancer 86(4):596–604. https://doi.org/10.1038/sj.bjc.6600111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Abel F, Sjoberg RM, Krona C, Nilsson S, Martinsson T (2004) Mutations in the N-terminal domain of DFF45 in a primary germ cell tumor and in neuroblastoma tumors. Int J Oncol 25(5):1297–1302

    CAS  PubMed  Google Scholar 

  89. Takahashi M, Ozaki T, Takahashi A, Miyauchi M, Ono S, Takada N, Koda T, Todo S, Kamijo T, Nakagawara A (2007) DFF45/ICAD restores cisplatin-induced nuclear fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells. Oncogene 26(38):5669–5673. https://doi.org/10.1038/sj.onc.1210352

    Article  CAS  PubMed  Google Scholar 

  90. Yao Y, Dai W (2014) Genomic instability and cancer. J Carcinog Mutagen. https://doi.org/10.4172/2157-2518.1000165

    Article  PubMed  PubMed Central  Google Scholar 

  91. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194(4260):23–28

    Article  CAS  PubMed  Google Scholar 

  92. Crews L, Patrick C, Adame A, Rockenstein E, Masliah E (2011) Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer’s disease. Cell Death Dis 2(2):e120. https://doi.org/10.1038/cddis.2011.2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Stanga S, Lanni C, Govoni S, Uberti D, D’Orazi G, Racchi M (2010) Unfolded p53 in the pathogenesis of Alzheimer’s disease: is HIPK2 the link? Aging (Albany NY) 2(9):545–554. https://doi.org/10.18632/aging.100205

    Article  CAS  Google Scholar 

  94. Fujita T, Ishikawa Y (2011) Apoptosis in heart failure. The role of the beta-adrenergic receptor-mediated signaling pathway and p53-mediated signaling pathway in the apoptosis of cardiomyocytes. Circ J 75(8):1811–1818

    Article  CAS  PubMed  Google Scholar 

  95. Whelan RS, Kaplinskiy V, Kitsis RN (2010) Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu Rev Physiol 72:19–44. https://doi.org/10.1146/annurev.physiol.010908.163111

    Article  CAS  PubMed  Google Scholar 

  96. Eguchi K (2001) Apoptosis in autoimmune diseases. Intern Med 40(4):275–284

    Article  CAS  PubMed  Google Scholar 

  97. Nagata S (2007) Autoimmune diseases caused by defects in clearing dead cells and nuclei expelled from erythroid precursors. Immunol Rev 220:237–250. https://doi.org/10.1111/j.1600-065X.2007.00571.x

    Article  CAS  PubMed  Google Scholar 

  98. Dunkle A, Dzhagalov I, He YW (2011) Cytokine-dependent and cytokine-independent roles for Mcl-1: genetic evidence for multiple mechanisms by which Mcl-1 promotes survival in primary T lymphocytes. Cell Death Dis 2:e214. https://doi.org/10.1038/cddis.2011.95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tamiya S, Etoh K, Suzushima H, Takatsuki K, Matsuoka M (1998) Mutation of CD95 (Fas/Apo-1) gene in adult T-cell leukemia cells. Blood 91(10):3935–3942

    Article  CAS  PubMed  Google Scholar 

  100. El Hindy N, Bachmann HS, Lambertz N, Adamzik M, Nuckel H, Worm K, Zhu Y, Sure U, Siffert W, Sandalcioglu IE (2011) Association of the CC genotype of the regulatory BCL2 promoter polymorphism (-938C>A) with better 2-year survival in patients with glioblastoma multiforme. J Neurosurg 114(6):1631–1639. https://doi.org/10.3171/2010.12.Jns10478

    Article  PubMed  Google Scholar 

  101. Yin C, Knudson CM, Korsmeyer SJ, Van Dyke T (1997) Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 385(6617):637–640. https://doi.org/10.1038/385637a0

    Article  CAS  PubMed  Google Scholar 

  102. Shen Z (2011) Genomic instability and cancer: an introduction. J Mol Cell Biol 3(1):1–3. https://doi.org/10.1093/jmcb/mjq057

    Article  CAS  PubMed  Google Scholar 

  103. Aguilera A, Garcia-Muse T (2013) Causes of genome instability. Annu Rev Genet 47:1–32. https://doi.org/10.1146/annurev-genet-111212-133232

    Article  CAS  PubMed  Google Scholar 

  104. Yamaguchi K, Uzzo R, Dulin N, Finke JH, Kolenko V (2004) Renal carcinoma cells undergo apoptosis without oligonucleosomal DNA fragmentation. Biochem Biophys Res Commun 318(3):710–713. https://doi.org/10.1016/j.bbrc.2004.04.086

    Article  CAS  PubMed  Google Scholar 

  105. Miles MA, Hawkins CJ (2017) Executioner caspases and CAD are essential for mutagenesis induced by TRAIL or vincristine. Cell Death Dis 8(10):e3062. https://doi.org/10.1038/cddis.2017.454

    Article  PubMed  PubMed Central  Google Scholar 

  106. Lovric MM, Hawkins CJ (2010) TRAIL treatment provokes mutations in surviving cells. Oncogene 29(36):5048–5060. https://doi.org/10.1038/onc.2010.242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Luciano F, Ricci JE, Herrant M, Bertolotto C, Mari B, Cousin JL, Auberger P (2002) T and B leukemic cell lines exhibit different requirements for cell death: correlation between caspase activation, DFF40/DFF45 expression, DNA fragmentation and apoptosis in T cell lines but not in Burkitt’s lymphoma. Leukemia 16(4):700–707. https://doi.org/10.1038/sj.leu.2402401

    Article  CAS  PubMed  Google Scholar 

  108. Yan B, Wang H, Peng Y, Hu Y, Wang H, Zhang X, Chen Q, Bedford JS, Dewhirst MW, Li C-Y (2006) A unique role of the DNA fragmentation factor in maintaining genomic stability. Proc Natl Acad Sci USA 103(5):1504–1509. https://doi.org/10.1073/pnas.0507779103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yan B, Wang H, Xie D, Wakamatsu N, Anscher MS, Dewhirst MW, Mitchel RE, Chen BJ, Li CY (2009) Increased skin carcinogenesis in caspase-activated DNase knockout mice. Carcinogenesis 30(10):1776–1780. https://doi.org/10.1093/carcin/bgp146

    Article  CAS  PubMed  Google Scholar 

  110. Deweese JE, Osheroff N (2009) The DNA cleavage reaction of topoisomerase II: wolf in sheep’s clothing. Nucleic Acids Res 37(3):738–748. https://doi.org/10.1093/nar/gkn937

    Article  CAS  PubMed  Google Scholar 

  111. Felix CA, Hosler MR, Winick NJ, Masterson M, Wilson AE, Lange BJ (1995) ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children. Blood 85(11):3250–3256

    Article  CAS  PubMed  Google Scholar 

  112. McClendon AK, Osheroff N (2007) DNA topoisomerase II, genotoxicity, and cancer. Mutat Res 623(1–2):83–97. https://doi.org/10.1016/j.mrfmmm.2007.06.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kalashnikova AA, Rogge RA, Hansen JC (2016) Linker histone H1 and protein-protein interactions. Biochim Biophys Acta 1859(3):455–461. https://doi.org/10.1016/j.bbagrm.2015.10.004

    Article  CAS  PubMed  Google Scholar 

  114. Izquierdo-Bouldstridge A, Bustillos A, Bonet-Costa C, Aribau-Miralbés P, García-Gomis D, Dabad M, Esteve-Codina A, Pascual-Reguant L, Peiró S, Esteller M, Murtha M, Millán-Ariño L, Jordan A (2017) Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats. Nucleic Acids Res 45(20):11622–11642. https://doi.org/10.1093/nar/gkx746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Krynetskaia NF, Phadke MS, Jadhav SH, Krynetskiy EY (2009) Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage. Mol Cancer Ther 8(4):864–872. https://doi.org/10.1158/1535-7163.Mct-08-0695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lu C, Zhu F, Cho YY, Tang F, Zykova T, Ma WY, Bode AM, Dong Z (2006) Cell apoptosis: requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3. Mol Cell 23(1):121–132. https://doi.org/10.1016/j.molcel.2006.05.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lee SH, Kwon HM, Kim YJ, Lee KM, Kim M, Yoon BW (2004) Effects of hsp70.1 gene knockout on the mitochondrial apoptotic pathway after focal cerebral ischemia. Stroke 35(9):2195–2199. https://doi.org/10.1161/01.Str.0000136150.73891.14

    Article  PubMed  Google Scholar 

  118. Wang J, Lindahl T (2016) Maintenance of genome stability. Genomics Proteomics Bioinform 14(3):119–121. https://doi.org/10.1016/j.gpb.2016.06.001

    Article  Google Scholar 

  119. Hain KO, Colin DJ, Rastogi S, Allan LA, Clarke PR (2016) Prolonged mitotic arrest induces a caspase-dependent DNA damage response at telomeres that determines cell survival. Sci Rep 6:26766. https://doi.org/10.1038/srep26766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273(10):5858–5868

    Article  CAS  PubMed  Google Scholar 

  121. Kinner A, Wu W, Staudt C, Iliakis G (2008) Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res 36(17):5678–5694. https://doi.org/10.1093/nar/gkn550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Downs JA, Lowndes NF, Jackson SP (2000) A role for Saccharomyces cerevisiae histone H2A in DNA repair. Nature 408(6815):1001–1004. https://doi.org/10.1038/35050000

    Article  CAS  PubMed  Google Scholar 

  123. Reina-San-Martin B, Difilippantonio S, Hanitsch L, Masilamani RF, Nussenzweig A, Nussenzweig MC (2003) H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation. J Exp Med 197(12):1767–1778. https://doi.org/10.1084/jem.20030569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Podhorecka M, Skladanowski A, Bozko P (2010) H2AX phosphorylation: its role in DNA damage response and cancer therapy. J Nucleic Acids. https://doi.org/10.4061/2010/920161

    Article  PubMed  PubMed Central  Google Scholar 

  125. Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A (2004) H2AX: the histone guardian of the genome. DNA Repair (Amst) 3(8–9):959–967. https://doi.org/10.1016/j.dnarep.2004.03.024

    Article  CAS  Google Scholar 

  126. Shiotani B, Zou L (2009) ATR signaling at a glance. J Cell Sci 122:301–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Flynn RL, Zou L (2011) ATR: a master conductor of cellular responses to DNA replication stress. Trends Biochem Sci 36(3):133–140. https://doi.org/10.1016/j.tibs.2010.09.005

    Article  CAS  PubMed  Google Scholar 

  128. Ji J, Zhang Y, Redon CE, Reinhold WC, Chen AP, Fogli LK, Holbeck SL, Parchment RE, Hollingshead M, Tomaszewski JE, Dudon Q, Pommier Y, Doroshow JH, Bonner WM (2017) Phosphorylated fraction of H2AX as a measurement for DNA damage in cancer cells and potential applications of a novel assay. PLoS ONE 12(2):e0171582. https://doi.org/10.1371/journal.pone.0171582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Sharma A, Singh K, Almasan A (2012) Histone H2AX phosphorylation: a marker for DNA damage. Methods Mol Biol 920:613–626. https://doi.org/10.1007/978-1-61779-998-3_40

    Article  CAS  PubMed  Google Scholar 

  130. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9(3):153–166. https://doi.org/10.1038/nrc2602

    Article  CAS  PubMed  Google Scholar 

  131. Vermeulen K, Van Bockstaele DR, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36(3):131–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T (1998) Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391(6667):597–601. https://doi.org/10.1038/35404

    Article  CAS  PubMed  Google Scholar 

  133. Buchkovich K, Duffy LA, Harlow E (1989) The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 58(6):1097–1105

    Article  CAS  PubMed  Google Scholar 

  134. Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA (1992) Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 70(6):993–1006

    Article  CAS  PubMed  Google Scholar 

  135. Bradbury EM, Inglis RJ, Matthews HR (1974) Control of cell division by very lysine rich histone (F1) phosphorylation. Nature 247(5439):257–261

    Article  CAS  PubMed  Google Scholar 

  136. DiPaola RS (2002) To arrest or not to G(2)-M Cell-cycle arrest: commentary re: A. K. Tyagi et al., Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth inhibition, G(2)-M arrest, and apoptosis. Clin Cancer Res 8(11):3512–3519

    Google Scholar 

  137. Kousholt AN, Menzel T, Sorensen CS (2012) Pathways for genome integrity in G2 phase of the cell cycle. Biomolecules 2(4):579–607. https://doi.org/10.3390/biom2040579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bernal A, Tusell L (2018) Telomeres: implications for cancer development. Int J Mol Sci. https://doi.org/10.3390/ijms19010294

    Article  PubMed  PubMed Central  Google Scholar 

  139. de Lange T (2004) T-loops and the origin of telomeres. Nat Rev Mol Cell Biol 5(4):323–329. https://doi.org/10.1038/nrm1359

    Article  CAS  PubMed  Google Scholar 

  140. Nikitina T, Woodcock CL (2004) Closed chromatin loops at the ends of chromosomes. J Cell Biol 166(2):161–165. https://doi.org/10.1083/jcb.200403118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Van Ly D, Low RRJ, Frolich S, Bartolec TK, Kafer GR, Pickett HA, Gaus K, Cesare AJ (2018) Telomere loop dynamics in chromosome end protection. Mol Cell 71(4):510-525 e516. https://doi.org/10.1016/j.molcel.2018.06.025

    Article  CAS  PubMed  Google Scholar 

  142. Li X, Manley JL (2005) Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122(3):365–378. https://doi.org/10.1016/j.cell.2005.06.008

    Article  CAS  PubMed  Google Scholar 

  143. Critchlow SE, Bowater RP, Jackson SP (1997) Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Curr Biol 7(8):588–598. https://doi.org/10.1016/s0960-9822(06)00258-2

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Servier Medical Art (http://smart.servier.com/) for the access to the images used to create the figures. NBP is an intern in veterinary neurology/neurosurgery, MK is a MD-PhD student.

Funding

This work was supported by a NSERC operating Grant 1257509 to JB.

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Authors and Affiliations

  1. INRS – Centre Armand-Frappier-Santé-Biotechnologie, 531 Boul. des Prairies, Laval, QC, H7V 1B7, Canada

    Merve Kulbay & Jacques Bernier

  2. Department of Medicine, Université de Montréal, 2900 Blvd. Edouard Montpetit, Montreal, QC, Canada

    Merve Kulbay

  3. Toronto Animal Health Partners Emergency and Specialty Hospital, 1 Scarsdale Road, North York, ON, M3B 2R2, Canada

    Nathan Bernier-Parker

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MK performed the literature search and designed the figures; MK, NBP and JB wrote the manuscript. JB guided during the writing process and revised the manuscript. All authors approve the final manuscript.

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Correspondence to Jacques Bernier.

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Kulbay, M., Bernier-Parker, N. & Bernier, J. The role of the DFF40/CAD endonuclease in genomic stability. Apoptosis 26, 9–23 (2021). https://doi.org/10.1007/s10495-020-01649-7

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