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Caspase-2 regulates S-phase cell cycle events to protect from DNA damage accumulation independent of apoptosis

A Correction to this article was published on 15 June 2022

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Abstract

In addition to its classical role in apoptosis, accumulating evidence suggests that caspase-2 has non-apoptotic functions, including regulation of cell division. Loss of caspase-2 is known to increase proliferation rates but how caspase-2 is regulating this process is currently unclear. We show that caspase-2 is activated in dividing cells in G1-phase of the cell cycle. In the absence of caspase-2, cells exhibit numerous S-phase defects including delayed exit from S-phase, defects in repair of chromosomal aberrations during S-phase, and increased DNA damage following S-phase arrest. In addition, caspase-2-deficient cells have a higher frequency of stalled replication forks, decreased DNA fiber length, and impeded progression of DNA replication tracts. This indicates that caspase-2 protects from replication stress and promotes replication fork protection to maintain genomic stability. These functions are independent of the pro-apoptotic function of caspase-2 because blocking caspase-2-induced cell death had no effect on cell division, DNA damage-induced cell cycle arrest, or DNA damage. Thus, our data supports a model where caspase-2 regulates cell cycle and DNA repair events to protect from the accumulation of DNA damage independently of its pro-apoptotic function.

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Fig. 1: Caspase-2 limits cellular proliferation.
Fig. 2: Caspase-2 is activated in dividing cells.
Fig. 3: Loss of caspase-2 results in delayed exit from S-Phase following arrest.
Fig. 4: Loss of caspase-2 is associated with stalled replication forks.
Fig. 5: Loss of caspase-2 is associated with increased DNA damage and impaired DNA repair.
Fig. 6: The impact of caspase-2 loss on cell cycle checkpoints.
Fig. 7: The role of caspase-2 in cell division is independent of its ability to induce apoptosis.
Fig. 8: Loss of caspase-2 leads to faster recovery from mild DNA damage.

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References

  1. Boice A, Bouchier-Hayes L. Targeting apoptotic caspases in cancer. Biochimica Et Biophysica Acta Mol Cell Res. 2020;1867:118688.

    Article  CAS  Google Scholar 

  2. Bouchier-Hayes L. The role of caspase-2 in stress-induced apoptosis. J Cell Mol Med. 2010;14:1212–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bouchier-Hayes L, Green DR. Caspase-2: the orphan caspase. Cell Death Differ. 2012;19:51–7.

    Article  CAS  PubMed  Google Scholar 

  4. Ho LH, Taylor R, Dorstyn L, Cakouros D, Bouillet P, Kumar S. A tumor suppressor function for caspase-2. Proc Natl Acad Sci USA. 2009;106:5336–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Puccini J, Shalini S, Voss AK, Gatei M, Wilson CH, Hiwase DK, et al. Loss of caspase-2 augments lymphomagenesis and enhances genomic instability in Atm-deficient mice. Proc Natl Acad Sci USA. 2013;110:19920–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Terry MR, Arya R, Mukhopadhyay A, Berrett KC, Clair PM, Witt B, et al. Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo. Cell Death Differ. 2015;22:719–30.

    Article  CAS  PubMed  Google Scholar 

  7. Parsons MJ, McCormick L, Janke L, Howard A, Bouchier-Hayes L, Green DR. Genetic deletion of caspase-2 accelerates MMTV/c-neu-driven mammary carcinogenesis in mice. Cell Death Differ. 2013;20:1174–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ren K, Lu J, Porollo A, Du C. Tumor-suppressing function of caspase-2 requires catalytic site Cys-320 and site Ser-139 in mice. J Biol Chem. 2012;287:14792–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tinel A, Tschopp J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science. 2004;304:843–6.

    Article  CAS  PubMed  Google Scholar 

  10. Berube C, Boucher LM, Ma W, Wakeham A, Salmena L, Hakem R, et al. Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD. Proc Natl Acad Sci USA. 2005;102:14314–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Oliver TG, Meylan E, Chang GP, Xue W, Burke JR, Humpton TJ, et al. Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop. Mol Cell. 2011;43:57–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fava LL, Schuler F, Sladky V, Haschka MD, Soratroi C, Eiterer L, et al. The PIDDosome activates p53 in response to supernumerary centrosomes. Genes Dev. 2017;31:34–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Baptiste-Okoh N, Barsotti AM, Prives C. A role for caspase 2 and PIDD in the process of p53-mediated apoptosis. Proc Natl Acad Sci USA. 2008;105:1937–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science. 2002;297:1352–4.

    Article  CAS  PubMed  Google Scholar 

  15. Robertson JD, Enoksson M, Suomela M, Zhivotovsky B, Orrenius S. Caspase-2 acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis. J Biol Chem. 2002;277:29803–9.

    Article  CAS  PubMed  Google Scholar 

  16. Baptiste-Okoh N, Barsotti A, Prives C. A role for caspase 2 and PIDD in the process of p53-mediated apoptosis. Proc Natl Acad Sci USA. 2008;105:1937–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sidi S, Sanda T, Kennedy RD, Hagen AT, Jette CA, Hoffmans R, et al. Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3. Cell. 2008;133:864–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pan Y, Ren KH, He HW, Shao RG. Knockdown of Chk1 sensitizes human colon carcinoma HCT116 cells in a p53-dependent manner to lidamycin through abrogation of a G2/M checkpoint and induction of apoptosis. Cancer Biol Ther. 2009;8:1559–66.

    Article  CAS  PubMed  Google Scholar 

  19. Ando K, Parsons MJ, Shah RB, Charendoff CI, Paris SL, Liu PH, et al. NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus. J Cell Biol. 2017;216:1795–810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Robeson AC, Lindblom KR, Wojton J, Kornbluth S, Matsuura K. Dimer-specific immunoprecipitation of active caspase-2 identifies TRAF proteins as novel activators. EMBO J. 2018;37:e97072.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bouchier-Hayes L, Oberst A, McStay GP, Connell S, Tait SW, Dillon CP, et al. Characterization of cytoplasmic caspase-2 activation by induced proximity. Mol Cell. 2009;35:830–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Manzl C, Krumschnabel G, Bock F, Sohm B, Labi V, Baumgartner F, et al. Caspase-2 activation in the absence of PIDDosome formation. J Cell Biol. 2009;185:291–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nitiss J, Wang JC. DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc Natl Acad Sci. 1988;85:7501–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Goldwasser F, Shimizu T, Jackman J, Hoki Y, O’Connor PM, Kohn KW, et al. Correlations between S and G2 arrest and the cytotoxicity of camptothecin in human colon carcinoma cells. Cancer Res. 1996;56:4430–7.

    CAS  PubMed  Google Scholar 

  25. Nelson WG, Kastan MB. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol Cell Biol. 1994;14:1815–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Saintigny Y, Delacote F, Vares G, Petitot F, Lambert S, Averbeck D, et al. Characterization of homologous recombination induced by replication inhibition in mammalian cells. EMBO J. 2001;20:3861–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gundry MC, Brunetti L, Lin A, Mayle AE, Kitano A, Wagner D, et al. Highly efficient genome editing of murine and human hematopoietic progenitor cells by CRISPR/Cas9. Cell Rep. 2016;17:1453–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Moreno-Mateos MA, Vejnar CE, Beaudoin JD, Fernandez JP, Mis EK, Khokha MK, et al. CRISPRscan: designing highly efficient sgRNAs for CRISPR-Cas9 targeting in vivo. Nat Methods. 2015;12:982–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lapytsko A, Kollarovic G, Ivanova L, Studencka M, Schaber J. FoCo: a simple and robust quantification algorithm of nuclear foci. BMC Bioinformatics. 2015;16:392.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Krull A, Buchholz T-O, Jug F. Noise2Void - learning denoising from single noisy images. 2019 Ieee Cvf Conf Comput Vis Pattern Recognit Cvpr. 2019;00:2124–32.

    Google Scholar 

  31. von Chamier L, Laine RF, Jukkala J, Spahn C, Krentzel D, Nehme E, et al. Democratising deep learning for microscopy with ZeroCostDL4Mic. Nat Commun. 2021;12:2276.

    Article  Google Scholar 

  32. Stringer C, Wang T, Michaelos M, Pachitariu M. Cellpose: a generalist algorithm for cellular segmentation. Nat Methods. 2021;18:100–6.

    Article  CAS  PubMed  Google Scholar 

  33. Singh M, Hunt CR, Pandita RK, Kumar R, Yang CR, Horikoshi N, et al. Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest. Mol Cell Biol. 2013;33:1210–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sharma GG, Hwang KK, Pandita RK, Gupta A, Dhar S, Parenteau J, et al. Human heterochromatin protein 1 isoforms HP1(Hsalpha) and HP1(Hsbeta) interfere with hTERT-telomere interactions and correlate with changes in cell growth and response to ionizing radiation. Mol Cell Biol. 2003;23:8363–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hunt CR, Dix DJ, Sharma GG, Pandita RK, Gupta A, Funk M, et al. Genomic instability and enhanced radiosensitivity in Hsp70.1- and Hsp70.3-deficient mice. Mol Cell Biol. 2004;24:899–911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Baliga BC, Read SH, Kumar S. The biochemical mechanism of caspase-2 activation. Cell Death Differ. 2004;11:1234–41.

    Article  CAS  PubMed  Google Scholar 

  37. Nishitani H, Lygerou Z, Nishimoto T. Proteolysis of DNA replication licensing factor Cdt1 in S-phase is performed independently of geminin through its N-terminal region. J Biol Chem. 2004;279:30807–16.

    Article  CAS  PubMed  Google Scholar 

  38. Sakaue-Sawano A, Kurokawa H, Morimura T, Hanyu A, Hama H, Osawa H, et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell. 2008;132:487–98.

    Article  CAS  PubMed  Google Scholar 

  39. Nishitani H, Taraviras S, Lygerou Z, Nishimoto T. The human licensing factor for DNA replication Cdt1 accumulates in G1 and is destabilized after initiation of S-phase. J Biol Chem. 2001;276:44905–11.

    Article  CAS  PubMed  Google Scholar 

  40. Bianchi V, Pontis E, Reichard P. Changes of deoxyribonucleoside triphosphate pools induced by hydroxyurea and their relation to DNA synthesis. J Biol Chem. 1986;261:16037–42.

    Article  CAS  PubMed  Google Scholar 

  41. Singh DK, Pandita RK, Singh M, Chakraborty S, Hambarde S, Ramnarain D, et al. MOF Suppresses Replication Stress and Contributes to Resolution of Stalled Replication Forks. Mol Cell Biol. 2018;38:e00484–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Saintigny Y. Characterization of homologous recombination induced by replication inhibition in mammalian cells. EMBO J. 2001;20:3861–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273:5858–68.

    Article  CAS  PubMed  Google Scholar 

  44. Mattoo AR, Pandita RK, Chakraborty S, Charaka V, Mujoo K, Hunt CR, et al. MCL-1 Depletion Impairs DNA Double-Strand Break Repair and Reinitiation of Stalled DNA Replication Forks. Mol Cell Biol. 2017;37:e00535–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003;300:1542–8.

    Article  CAS  PubMed  Google Scholar 

  46. Sanchez Y. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science. 1997;277:1497–501.

    Article  CAS  PubMed  Google Scholar 

  47. Mailand N. Rapid destruction of human Cdc25A in response to DNA damage. Science. 2000;288:1425–9.

    Article  CAS  PubMed  Google Scholar 

  48. Liu S, Shiotani B, Lahiri M, Marechal A, Tse A, Leung CC, et al. ATR autophosphorylation as a molecular switch for checkpoint activation. Mol Cell. 2011;43:192–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Falck J, Petrini JHJ, Williams BR, Lukas J, Bartek J. The DNA damage-dependent intra–S phase checkpoint is regulated by parallel pathways. Nat Genet. 2002;30:290–4.

    Article  PubMed  Google Scholar 

  50. Matsuoka S, Huang M, Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998;282:1893–7.

    Article  CAS  PubMed  Google Scholar 

  51. Ismail IH, Nyström S, Nygren J, Hammarsten O. Activation of ataxia telangiectasia mutated by DNA strand break-inducing agents correlates closely with the number of DNA double strand breaks. J Biol Chem. 2005;280:4649–55.

    Article  CAS  PubMed  Google Scholar 

  52. Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES. Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J Biol Chem. 2002;277:13430–7.

    Article  CAS  PubMed  Google Scholar 

  53. Bonzon C, Bouchier-Hayes L, Pagliari LJ, Green DR, Newmeyer DD. Caspase-2-induced apoptosis requires bid cleavage: a physiological role for bid in heat shock-induced death. Mol Biol Cell. 2006;17:2150–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Howard A. Synthesis of deoxyribonucleic acid in normal and irradiated ceils and its relation to chromosome breakage. Heredity Suppl. 1953;6:261–73.

    CAS  Google Scholar 

  55. Kuzminov A. Collapse and repair of replication forks in Escherichia coli. Mol Microbiol. 1995;16:373–84.

    Article  CAS  PubMed  Google Scholar 

  56. Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nat Cell Biol. 2014;16:2–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, et al. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell. 2011;145:435–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Beck H, Nahse-Kumpf V, Larsen MS, O’Hanlon KA, Patzke S, Holmberg C, et al. Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol Cell Biol. 2012;32:4226–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lopez-Garcia C, Sansregret L, Domingo E, McGranahan N, Hobor S, Birkbak NJ, et al. BCL9L dysfunction impairs caspase-2 expression permitting aneuploidy tolerance in colorectal cancer. Cancer cell. 2017;31:79–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dawar S, Lim Y, Puccini J, White M, Thomas P, Bouchier-Hayes L, et al. Caspase-2-mediated cell death is required for deleting aneuploid cells. Oncogene. 2017;36:2704–14.

    Article  CAS  PubMed  Google Scholar 

  61. Paulovich AG, Hartwell LH. A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell. 1995;82:841–7.

    Article  CAS  PubMed  Google Scholar 

  62. Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 2005;19:1040–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response. Mol Cell. 2017;66:801–17.

    Article  CAS  PubMed  Google Scholar 

  64. Saldivar JC, Cortez D, Cimprich KA. The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat Rev Mol Cell Biol. 2017;18:622–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang H, Wang H, Powell SN, Iliakis G, Wang Y. ATR affecting cell radiosensitivity is dependent on homologous recombination repair but independent of nonhomologous end joining. Cancer Res. 2004;64:7139–43.

    Article  CAS  PubMed  Google Scholar 

  66. Couch FB, Bansbach CE, Driscoll R, Luzwick JW, Glick GG, Betous R, et al. ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev. 2013;27:1610–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ceccaldi R, Sarangi P, D’Andrea AD. The Fanconi anaemia pathway: new players and new functions. Nat Rev Mol Cell Biol. 2016;17:337–49.

    Article  CAS  PubMed  Google Scholar 

  68. Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 2001;15:2177–96.

    Article  CAS  PubMed  Google Scholar 

  69. Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, et al. ATM associates with and phosphorylates p53: mapping the region of interaction. Nat Genet. 1998;20:398–400.

    Article  CAS  PubMed  Google Scholar 

  70. Gatei M, Scott SP, Filippovitch I, Soronika N, Lavin MF, Weber B, et al. Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res. 2000;60:3299–304.

    CAS  PubMed  Google Scholar 

  71. Lim D-S, Kim S-T, Xu B, Maser RS, Lin J, Petrini JHJ, et al. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature. 2000;404:613–7.

    Article  CAS  PubMed  Google Scholar 

  72. Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci. 2000;97:10389–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chaturvedi P, Eng WK, Zhu Y, Mattern MR, Mishra R, Hurle MR, et al. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene. 1999;18:4047–54.

    Article  CAS  PubMed  Google Scholar 

  74. Brown AL, Lee CH, Schwarz JK, Mitiku N, Piwnica-Worms H, Chung JH. A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. Proc Natl Acad Sci. 1999;96:3745–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhong Y, Nellimoottil T, Peace JM, Knott SR, Villwock SK, Yee JM, et al. The level of origin firing inversely affects the rate of replication fork progression. J Cell Biol. 2013;201:373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Andersen JL, Johnson CE, Freel CD, Parrish AB, Day JL, Buchakjian MR, et al. Restraint of apoptosis during mitosis through interdomain phosphorylation of caspase-2. Embo J. 2009;20:3216–27.

    Article  Google Scholar 

  77. Lim Y, De Bellis D, Sandow JJ, Capalbo L, D'Avino PP, Murphy JM, et al. Phosphorylation by Aurora B kinase regulates caspase-2 activity and function. Cell Death Differ. 2020;28:349–66.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Nurse P. Universal control mechanism regulating onset of M-phase. Nature. 1990;344:503–8.

    Article  CAS  PubMed  Google Scholar 

  79. Glover DM, Leibowitz MH, McLean DA, Parry H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell. 1995;81:95–105.

    Article  CAS  PubMed  Google Scholar 

  80. Gao Z, Shao Y, Jiang X. Essential roles of the Bcl-2 family of proteins in caspase-2-induced apoptosis. J Biol Chem. 2005;280:38271–5.

    Article  CAS  PubMed  Google Scholar 

  81. Lin Y-F, Shih H-Y, Shang Z-F, Kuo C-T, Guo J, Du C, et al. PIDD mediates the association of DNA-PKcs and ATR at stalled replication forks to facilitate the ATR signaling pathway. Nucleic Acids Res. 2018;46:1847–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Henry CM, Martin SJ. Caspase-8 acts in a non-enzymatic role as a scaffold for assembly of a pro-inflammatory “FADDosome” Complex upon TRAIL Stimulation. Mol Cell. 2017;65:715–29 e715.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Jennifer Martinez (NIEHS) for careful reading of this paper. Funding for this project includes NIH/NIGMS R01GM121389 (LBH), NIH/NCI R21CA256606 (LBH) and NIH/NIGMS T32GM008231 (KEL). This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (P30 AI036211, P30 CA125123, and S10 RR024574) and the expert assistance of J. M. Sederstrom. We would like to acknowledge the Texas Children’s Hospital William T. Shearer Center for Human Immunobiology for their generous support for this research and the expert assistance of Rebecca Kairis.

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AGB, KEL, MJP, TKP, and LB-H conceived and designed experiments. AGB, KEL, RKP, MJP, CIC, and VC performed the experiments. AFC developed the imaging analysis. AGB and LB-H wrote the paper.

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Correspondence to Lisa Bouchier-Hayes.

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MJP is currently employed at BD Biosciences. The remaining authors have no conflict of interest.

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Boice, A.G., Lopez, K.E., Pandita, R.K. et al. Caspase-2 regulates S-phase cell cycle events to protect from DNA damage accumulation independent of apoptosis. Oncogene 41, 204–219 (2022). https://doi.org/10.1038/s41388-021-02085-w

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