Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance

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dc.contributor.authorVainshelbaum, Ninel Miriam
dc.contributor.authorSalmina, Kristine
dc.contributor.authorGerashchenko, Bogdan I.
dc.contributor.authorLazovska, Marija
dc.contributor.authorZayakin, Pawel
dc.contributor.authorCragg, Mark Steven
dc.contributor.authorPjanova, Dace
dc.contributor.authorErenpreisa, Jekaterina
dc.date.accessioned2022-11-11T14:10:01Z
dc.date.available2022-11-11T14:10:01Z
dc.date.issued2022-03-01
dc.descriptionFunding Information: Funding: This research was funded by the University of Latvia Foundation’s PhD Student Scholarship in the Natural and Life Sciences (awarded to N.M.V.), a grant from the European Regional Development Fund (ERDF) projects No. 1.1.1.2/VIAA/3/19/463 for K.S. and ERDF 099 project No. 1.1.1.1/18/A/099) for D.P. and J.E. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
dc.description.abstractHere, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. However, it is deregulated in embryonic stem cells (ESCs), the early embryo, and cancer. Here, we review the DNA damage response of cancer cells and a similar impact on the cell cycle to that found in ESCs—overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, coupling telomere erosion to accelerated cell senescence, and favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Polyploidy decelerates the CC. We report an intriguing positive correlation between cancer WGD and the deregulation of the CC assessed by bioinformatics on 11 primary cancer datasets (rho = 0.83; p < 0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by ALT-recombination, and return their depolyploidised offspring to telomerase-dependent regulation. By reversing this polyploidy and the CC “death loop”, the mitotic cycle and Hayflick limit count are thus again renewed. Our review and proposed mechanism support a life-cycle concept of cancer and highlight the perspective of cancer treatment by differentiation.en
dc.description.statusPeer reviewed
dc.format.extent2408187
dc.identifier.citationVainshelbaum, N M, Salmina, K, Gerashchenko, B I, Lazovska, M, Zayakin, P, Cragg, M S, Pjanova, D & Erenpreisa, J 2022, 'Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance', Cells, vol. 11, no. 5, 880. https://doi.org/10.3390/cells11050880
dc.identifier.doi10.3390/cells11050880
dc.identifier.issn2073-4409
dc.identifier.urihttps://dspace.rsu.lv/jspui/handle/123456789/9775
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85126024402&partnerID=8YFLogxK
dc.language.isoeng
dc.relation.ispartofCells
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectCancer resistance
dc.subjectCell cycle
dc.subjectCircadian clock (CC)
dc.subjectDNA damage response (DDR)
dc.subjectGenotoxic treatments
dc.subjectHayflick limit
dc.subjectReprogramming
dc.subjectReversible polyploidy
dc.subjectSenescence
dc.subjectTelomeres
dc.subject1.6 Biological sciences
dc.subject3.1 Basic medicine
dc.subject1.1. Scientific article indexed in Web of Science and/or Scopus database
dc.subjectGeneral Biochemistry,Genetics and Molecular Biology
dc.subjectSDG 3 - Good Health and Well-being
dc.titleRole of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistanceen
dc.type/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article

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