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Discovery of a new biological rhythm

By carrying out dry mass measurements on different types of human cells, IRIG researchers in collaboration with CEA-Leti have demonstrated the existence of a new biological rhythm lasting 4 hours and manifesting itself between two cell divisions. These results contribute to the current understanding of ultradian biological clocks and could potentially have strong implications in the field of health.

Published on 7 December 2020
The synthesis of proteins and their degradation play a major role in the way our cells function, in particular by helping to maintain the abundance of proteins. They do this by allowing the recycling of elementary components (amino acids), favouring normal biological functions. The abundance of proteins in the cell is regulated in a complex way at the transcriptional, translational and post-translational levels. One of the dominant regulatory pathways of protein degradation occurs via the Ubiquitin-Proteasome system, perturbation of which can lead to pathologies as diverse and varied as cancers, neuronal disorders It is, however, still not well understood how the protein ubiquitination and degradation kinetics affect the dynamics of the protein network and maintain their homeostasis (equilibrium).

Using lensless imaging to make measurements of dry mass (constituted principally of proteins), IRIG researchers uncovered a new biological rhythm in a variety of human cells. This rhythm is ultradian (its period is less than 24 hours) and appears between two successive cell divisions. It was observed on "native" cell populations, i.e. non-fluorescent and non-synchronized. Independent of the circadian rhythm, it has a periodicity of 4 hours and is insensitive to temperature, which is a characteristic of biological clocks. The researchers showed that this rhythm was suppressed by proteasome inhibitors and was only observed in proliferating cells, indicating that it reflects the periodic dynamics of the protein mass in the growing cells.

These results suggest new interesting hypotheses:
i) Besides the de novo synthesis of proteins necessary for cell growth, this massive protein recycling, occurring every 4 hours, may enable adaptation to acute microenvironmental changes at a low cost in energy.
ii) It could be a way to erase and “reboot”, every 4 hours, post-translational modifications of proteins.
iii) It may be part of a defense system against pathogens (massive pathogens degradation and antigen generation every 4 hours.

These results contribute to the current understanding of ultradian biological clocks, the Ubiquitin-Proteasome system, and cell cycle regulation. This may have significant implications in the field of health.

Pulsatile dynamics of the dry mass between two successive divisions of an individual cell, superimposed on its average growth. This was revealed by a spectral analysis allowing the signal to be extracted from the noise.
Quantitative study of the cycle of an individual cell (cell growth and proliferation) by lensless microscopy, deduced from the kinetics of thousands of cells followed in real time over a wide field of view (29.4 mm2), over periods of up to several days, and with a rapid acquisition rate (5 minutes).
The Ubiquitin-Proteasome system is a protein degradation pathway characterized by two successive events: first, labelling, via an ubiquitin ligase, of the substrates to be degraded by a polymer of ubiquitin molecules; and second, recognition, and then degradation of these poly-ubiquitinated substrates by a multi-protein enzymatic complex, the proteasome.
Lensless imaging allows the dynamic observation of cell life, simply and without labels, at both microscopic and mesoscopic scales, over a wide field of view and over a range of times from days to weeks.

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