Most human cells are diploid, containing two copies of each chromosome. They are also euploid, that is, the stability of the genome is maintained over time. These two conditions are important to allow cells to proliferate while maintaining their stability. Indeed, the induction of complete duplication of the genome or tetraploidy in initially diploid cells generates a strong genetic instability. The latter contributes to cancer development in which duplication of the genome has been demonstrated in approximately 40% of solid tumors. Nevertheless, the molecular origins of this genetic instability and, in particular, the immediate consequences of tetraploidy, were not known.

To better understand the consequences of tetraploidy, the first step was to develop an adequate study model. For this the scientists chose to use human cells in diploid and euploid culture in which they set up new tools to induce genome duplication. They then observed that tetraploid cells thus formed a very strong genetic instability, from the first S phase following this duplication of the genome. This results in (a) the accumulation of DNA breaks dependent on DNA replication and (b) the generation of a very abnormal karyotype in this single S phase. From a mechanistic point of view, these results demonstrate that the genetic instability of tetraploid cells is explained by the alteration of DNA replication dynamics. To understand these defects, the researchers measured the amount of protein in the tetraploid cells. Then they observed that tetraploid cells are not able to “sense” an increase in the amount of DNA and adapt the production of proteins accordingly. Thus, some of the key factors of DNA replication become limited to support the replication of double amounts of DNA. The lack of proportionality between the amount of DNA and the production of proteins is explained by the fact that tetraploid cells do not have enough time to produce the factors necessary for DNA replication before entering the stage. s. This is well illustrated by the fact that the genetic stability of tetraploid cells can be restored by increasing the duration of the G1 phase or alternatively by increasing the expression of DNA replication factors. Researchers also confirmed Live showing their observations involving multiple cycles of genome duplication in the neural stem cells of the larvae of K. Drosophila melanogaster Leads to the generation of DNA damage during its replication. And again, this damage is prevented by overexpression of the replication protein.

This study demonstrates that from the first S phase, tetraploid cells present a strong genetic instability. The latter may promote the accumulation of mutations involved in the proliferation and survival of these tetraploid cells, which may explain the high proportion of tetraploid tumors. In agreement with this model, the researchers demonstrated that tetraploid tumors presented an overexpression of DNA repair pathways compared with diploid tumors, clearly suggesting significant genetic instability in the tetraploid tumor context.

It now remains to be understood why tetraploid cells do not experience an increase in the amount of DNA. What adaptations are necessary to maintain genome stability as the amount of DNA increases? Indeed, some cells accumulate multiple copies of the genome during development and do this in a programmed manner without exhibiting genetic instability. Identifying the mechanisms that maintain genome stability in this context represents a promising future avenue of research.

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Genetic instability from a single S-phase followed by whole-genome duplication.
Simon Gamble, René Wardener, Christina Keper, Nishit Srivastava, Maddalena Nano, Anne-Sophie Messe, Andrea E. Tijuice, Sarah Vanessa Bernhard, Diana CJ Spearings, Anthony Simon, Oumo Goundium, Helfried 6 Hocheger, Matthew Piel, Floris Foijer, Zuzana Foijer Storchova and Renata Busto.
Nature March 30, 2022. https://doi.org/10.1038/s41586-022-04578-4