DNA Damage Checkpoints Balance a Tradeoff Between Diploid- and Polyploid-derived Arrest Failures

Overview

Journal bioRxiv

Date 2025 Feb 24

PMID 39990415

Authors

Kotaro Fujimaki

Ashwini Jambhekar

Galit Lahav

Affiliations

Soon will be listed here.

Abstract

The DNA damage checkpoint system ensures genomic integrity by preventing the division of damaged cells. This system operates primarily through the and checkpoints, which are susceptible to failure; how these checkpoints coordinate quantitatively to ensure optimal cellular outcomes remains unclear. In this study, we exposed non-cancerous human cells to exogenous DNA damage and used single-cell imaging to monitor spontaneous arrest failure. We discovered that cells fail to arrest in two major paths, resulting in two types with distinct characteristics, including ploidy, nuclear morphology, and micronuclei composition. Computational simulations and experiments revealed strengthening one checkpoint reduced one mode of arrest failure but increased the other, leading to a critical tradeoff for optimizing total arrest failure rates. Our findings suggest optimal checkpoint strengths for minimizing total error are inherently suboptimal for any single failure type, elucidating the systemic cause of genomic instability and tetraploid-like cells in response to DNA damage.

References

Kwon M, Leibowitz M, Lee J . Small but mighty: the causes and consequences of micronucleus rupture. Exp Mol Med. 2020; 52(11):1777-1786. PMC: 8080619. DOI: 10.1038/s12276-020-00529-z. View

Davoli T, de Lange T . The causes and consequences of polyploidy in normal development and cancer. Annu Rev Cell Dev Biol. 2011; 27:585-610. DOI: 10.1146/annurev-cellbio-092910-154234. View

Taylor W, Stark G . Regulation of the G2/M transition by p53. Oncogene. 2001; 20(15):1803-15. DOI: 10.1038/sj.onc.1204252. View

Krempler A, Deckbar D, Jeggo P, Lobrich M . An imperfect G2M checkpoint contributes to chromosome instability following irradiation of S and G2 phase cells. Cell Cycle. 2007; 6(14):1682-6. DOI: 10.4161/cc.6.14.4480. View

Khanna K, Lavin M, Jackson S, MULHERN T . ATM, a central controller of cellular responses to DNA damage. Cell Death Differ. 2001; 8(11):1052-65. DOI: 10.1038/sj.cdd.4400874. View

Suzuki M, Yamauchi M, Oka Y, Suzuki K, Yamashita S . Live-cell imaging visualizes frequent mitotic skipping during senescence-like growth arrest in mammary carcinoma cells exposed to ionizing radiation. Int J Radiat Oncol Biol Phys. 2012; 83(2):e241-50. DOI: 10.1016/j.ijrobp.2011.12.003. View

Mayer V, Aguilera A . High levels of chromosome instability in polyploids of Saccharomyces cerevisiae. Mutat Res. 1990; 231(2):177-86. DOI: 10.1016/0027-5107(90)90024-x. View

Krenning L, Feringa F, Shaltiel I, van den Berg J, Medema R . Transient activation of p53 in G2 phase is sufficient to induce senescence. Mol Cell. 2014; 55(1):59-72. DOI: 10.1016/j.molcel.2014.05.007. View

Reyes J, Chen J, Stewart-Ornstein J, Karhohs K, Mock C, Lahav G . Fluctuations in p53 Signaling Allow Escape from Cell-Cycle Arrest. Mol Cell. 2018; 71(4):581-591.e5. PMC: 6282757. DOI: 10.1016/j.molcel.2018.06.031. View

10.

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

11.

Huang L, Clarkin K, Wahl G . Sensitivity and selectivity of the DNA damage sensor responsible for activating p53-dependent G1 arrest. Proc Natl Acad Sci U S A. 1996; 93(10):4827-32. PMC: 39364. DOI: 10.1073/pnas.93.10.4827. View

12.

Nyberg K, Michelson R, Putnam C, Weinert T . Toward maintaining the genome: DNA damage and replication checkpoints. Annu Rev Genet. 2002; 36:617-56. DOI: 10.1146/annurev.genet.36.060402.113540. View

13.

Fujiwara T, Bandi M, Nitta M, Ivanova E, Bronson R, Pellman D . Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature. 2005; 437(7061):1043-7. DOI: 10.1038/nature04217. View

14.

Chao H, Poovey C, Privette A, Grant G, Chao H, Cook J . Orchestration of DNA Damage Checkpoint Dynamics across the Human Cell Cycle. Cell Syst. 2017; 5(5):445-459.e5. PMC: 5700845. DOI: 10.1016/j.cels.2017.09.015. View

15.

Levine A . p53, the cellular gatekeeper for growth and division. Cell. 1997; 88(3):323-31. DOI: 10.1016/s0092-8674(00)81871-1. View

16.

Xouri G, Lygerou Z, Nishitani H, Pachnis V, Nurse P, Taraviras S . Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines. Eur J Biochem. 2004; 271(16):3368-78. DOI: 10.1111/j.1432-1033.2004.04271.x. View

17.

Fava L, Schuler F, Sladky V, Haschka M, Soratroi C, Eiterer L . The PIDDosome activates p53 in response to supernumerary centrosomes. Genes Dev. 2017; 31(1):34-45. PMC: 5287111. DOI: 10.1101/gad.289728.116. View

18.

Linke S, Harris M, Neugebauer S, Clarkin K, Shepard H, Maneval D . p53-mediated accumulation of hypophosphorylated pRb after the G1 restriction point fails to halt cell cycle progression. Oncogene. 1997; 15(3):337-45. DOI: 10.1038/sj.onc.1201200. View

19.

Blackford A, Jackson S . ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Mol Cell. 2017; 66(6):801-817. DOI: 10.1016/j.molcel.2017.05.015. View

20.

Fukami J, ANNO K, Ueda K, Takahashi T, Ide T . Enhanced expression of cyclin D1 in senescent human fibroblasts. Mech Ageing Dev. 1995; 81(2-3):139-57. DOI: 10.1016/0047-6374(95)93703-6. View