Cellular senescence is a key physiological process in aging. It stops the renewal of a cell population after a certain number of generations. Cells that have reached this "age limit" irreversibly lose their ability to continue their cell cycle and, although still active, completely modify their metabolism and relationships with their environment. Their identification in vivo remains difficult due to the absence of universal "biomarkers" of cellular senescence.

Changes in the chromatin structure

Cellular senescence is accompanied by major changes in chromatin structure, which reflect, at least in part, changes in the level of expression of genes that the cell needs, for example, to stably repress certain proliferation genes and activate inflammation genes. Among the levers involved in these modifications, the composition of the nucleosome (which includes histones H2A, H2B, H3, and H4) and post-translational modifications of histones are prominent. In 2017, the senescence and genome stability team (I2BC), in collaboration with LEMM (SPI/DMTS) characterized the protein composition of the chromatin of senescent cells by mass spectrometry. To do this, the two teams combined two mass spectrometry analyses: a classical "bottom-up" analysis (after digestion of the proteins in the samples), and a "top-down" analysis, which has the advantage of giving a quick overview of the sequence modifications and of identifying the most abundant chemical modifications (and therefore the post-translational modifications). The researchers thus discovered that H2A.J, a histone H2A variant present only in mammals, accumulates in human fibroblasts during senescence due to DNA damage. 

Three new biomarkers?

In a recent paper published in Proteomes, the researchers continue their characterization of senescent cells and focus this time on histone H2B and two small proteins HMGA1 and HMGA2, as well as their isoforms and post-translational modifications. Using the same techniques as previously employed, they show that the H2B type 1-K variant is specifically enriched in cells undergoing deep senescence (20 days of senescence) and showing persistent DNA damage. This accumulation is related not only to an increase in transcription of the gene encoding the variant, but also to a post-transcriptional regulation (which could be an increase in translation and/or a slowing down of degradation...). The accumulation of the H2B type 1-K variant is not observed in quiescent cells or in cells undergoing senescence without DNA damage. Concerning HMGA proteins, the authors note the accumulation of di-methylated HMGA1a and tri-phosphorylated HMGA1b forms exclusively in the chromatin of cells in deep senescence with persistent DNA damage. 

Those modifications constitute potential new biomarkers of senescent cells containing persistent DNA damage.