Cell senescence, the seizing of the cell cycle, is ultimately a molecular process, but the molecular details have proved elusive. Yet if these details could be revealed, they might open new approaches to the treatment of cancer. Interrupting the cell cycle not would not only slow the proliferation of healthy cells, but also the growth of tumors.
One molecular event underlying cell senescence has emerged from a study of the chromatin environment, which can undergo changes that render it more or less hospitable to cell division. According to this study, changes to the structure of the protein histone H3.3 may play a key role in silencing genes that regulate cancer cell growth.
This study appeared November 14 in Nature Communications, in an article entitled, “Histone H3.3 and its proteolytically processed form drive a cellular senescence programme.”
The article describes how researchers from the Icahn School of Medicine at Mount Sinai used models of oncogene-induced and replicative senescence to investigate novel histone H3 tail cleavage events mediated by the protease Cathepsin L. The researchers, led by Emily Bernstein, Ph.D., found that cleaved forms of H3 are nucleosomal and that the histone variant H3.3 is the preferred cleaved form of H3.
The researchers also found that histone variant H3.3, a protein that works closely with chromatin to package and regulate genetic material within cells, and in particular its clipped form, help to silence target genes that regulate the cell cycle.
“Ectopic expression of H3.3 and its cleavage product (H3.3cs1), which lacks the first 21 amino acids of the H3 tail, is sufficient to induce senescence,” wrote the authors of the Nature Communications article. “Further, H3.3cs1 chromatin incorporation is mediated by the HUCA histone chaperone complex.”
“Genome-wide transcriptional profiling revealed that H3.3cs1 facilitates transcriptional silencing of cell cycle regulators including RB/E2F target genes,” the authors added, “likely via the permanent removal of H3K4me3.”
Ultimately, the researchers found that histone H3.3 and its proteolytically processed forms may serve to regulate cellular senescence, silencing genes that regulate cell division and duplication.
“Cellular senescence creates a chromatin environment that represses cell multiplication, and thus cell or tumor growth, but how this happens molecularly is what we sought to discover,” said Dr. Bernstein. “What we found was that histone H3.3 and its clipped form, which lacks 21 amino acids of the histone tail and associated modifications, prevents normal cells from dividing. Clipped H3.3 may be a marker of cells that stop proliferating and has implications for cancer, in particular cancers like melanoma that have a senescence phase.”