Showing papers by "Jekaterina Erenpreisa published in 2022"

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

Abstract: The Circadian Clock (CC) drives the normal cell cycle and reciprocally regulates telomere elongation. However, it can be deregulated in cancer, embryonic stem cells (ESC) and the early embryo. Here, its role in the resistance of cancer cells to genotoxic treatments was assessed in relation to whole-genome duplication (WGD) and telomere regulation. We first evaluated the DNA damage response of polyploid cancer cells and observed a similar impact on the cell cycle to that seen in ESC - overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, and coupling telomere erosion to accelerated cell senescence, favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Next, we revealed a positive correlation between cancer WGD and deregulation of 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 recombination and return their depolyploidised mitotic offspring to TERT-dependent telomere regulation. Through depolyploidisation and the CC ‘death loop’, the telomeres and Hayflick limit count are thus again renewed. This mechanism along with similar inactivity of the CC in early embryos supports a life-cycle (embryonic) concept of cancer.

The Transcriptome and Proteome Networks of Malignant Tumours Reveal Atavistic Attractors of Polyploidy-Related Asexual Reproduction

Abstract: The expression of gametogenesis-related (GG) genes and proteins, as well as whole genome duplications (WGD), are the hallmarks of cancer related to poor prognosis. Currently, it is not clear if these hallmarks are random processes associated only with genome instability or are programmatically linked. Our goal was to elucidate this via a thorough bioinformatics analysis of 1474 GG genes in the context of WGD. We examined their association in protein–protein interaction and coexpression networks, and their phylostratigraphic profiles from publicly available patient tumour data. The results show that GG genes are upregulated in most WGD-enriched somatic cancers at the transcriptome level and reveal robust GG gene expression at the protein level, as well as the ability to associate into correlation networks and enrich the reproductive modules. GG gene phylostratigraphy displayed in WGD+ cancers an attractor of early eukaryotic origin for DNA recombination and meiosis, and one relative to oocyte maturation and embryogenesis from early multicellular organisms. The upregulation of cancer–testis genes emerging with mammalian placentation was also associated with WGD. In general, the results suggest the role of polyploidy for soma–germ transition accessing latent cancer attractors in the human genome network, which appear as pre-formed along the whole Evolution of Life.

A New Perspective of Genome Regulation from the Physics of Life Standpoint

Abstract: Abstract The convergence between a statistical mechanics and biological approach in elucidating some basic features of cell differentiation opens new avenues of research in gene expression regulation and holds some promises in terms of a re-differentiation approach to a cancer cure. The message emerging from two recent papers by the authors of the present communication follows very simple basic lines. The time-honored concept of homeostasis, at the very basis of physiology, is in action even at the microscopic level of gene expression regulation, where a continuous (relatively small) oscillation of gene expression is mandatory for keeping alive the substantial stability of the gene expression profile typical of a given cell type. This mechanism of stability, when oscillation exceeds a certain threshold, is responsible for the spreading of a large-scale perturbation invading the entire genome and eventually giving rise to cell fate change. The material basis of this model was discovered in the onset of a global reorganisation of chromatin driven by fusion-splitting dynamics of pericentromeric associated domains that, by selective folding/unfolding of chromatin, allows for a global scale re-arrangement of genome expression.