The group of Chromatin Biology of the IDIBELL, led by Alex Vaquero, studies the role of a family of proteins called sirtuins in response to metabolic and genotoxic stress and their contribution to the development of diseases such ascancer and aging control.
In this study conducted in collaboration with the research group of Lourdes Serrano Institute of Human Genetics at Rutgers University in New Jersey (USA) and published in the journal Genes & Development, researchers describe epigenetic mechanisms whereby one of these proteins, the sirtuin 2 (SIRT2) regulates cell cycle progression and genomic stability.
Clinical applications of SIRT2
Recently, sirtuins, particularly SIRT1 and SIRT2, have been linked to neurodegenerative diseases. One of the many factors behind these disorders is oxidative stress and the primary response mechanism of our cells to these conditions is regulated for these proteins.
According to Àles Vaquero, “SirT1 seems to have a guard role against this type of stress while SIRT2 would have in many cases the opposite effect. The pharmaceutical industry seeks SIRT2 inhibitor drugs for use against these diseases. ”
The researcher notes that “for this reason it is important to know the tumor suppressor function of SIRT2, and it should be taken into account if, finally, it is offered as treatment.”
Control of epigenetic marks
Epigenetic modifications are chemical markers in the genome that result in changes in the expression of genes. One of these brands, the acetylation of the amino acid lysine 16 of histone H4 protein (H4K16Ac), appears to be particularly important in regulating the organization and genome integrity. Thus, alteration of this mark causes genome instability and has been linked directly to cancer.
A few years ago, Vaquero showed that SIRT2 regulates the removal of this epigenetic mark just before beginning the process of cell division (mitosis), probably to allow adequate compaction of chromosomes during mitosis.
In the study published now Genes & Development, IDIBELL researchers have explored the functional relationship between SIRT2, this epigenetic mark and mitosis, to try to understand the consequences of SIRT2 activity and loss of epigenetic marks H4K16Ac during mitosis and cell cycle in general.
Vaquero group found that the deacetylation (eliminating chemical mark) of lysine 16 on histone 4 by SIRT2 promotes the enzyme activity of PR-Set7 whose mission is to deposit another epigenetic mark, methylation, in a position very close to K16, lysine 20 of histone H4 same (H4K20me1). SIRT2 not only regulates the activity of PR-Set7 eliminating H4K16Ac also deacetylating PR-Set7 allowing the expansion of the mark throughout the genome.
“These marks” explained Vaquero “are key to the process of DNA replication and repair in the progression of mitosis, and chromatin compaction.”
“SIRT2 acts as the controlling agent: until conditions are right, it doesn’t continue the cell cycle” Vaquero explained. “We found that mice in the absence of SirT2, make mitosis and cell division but accumulates genetic damage and increased levels of genomic instability, so these animals are more likely to develop tumors.”
“In this job,” the researcher said “we have found the mechanism that confirms and explains the antitumor properties of SIRT2 and further linking the role of sirtuins in the control of cell epigenetic memory”.
Article’s reference
Serrano L., Martínez-Redondo P.*, Marazuela-Duques A.*, Vázquez N. B., Dooley S.J., Voigt P., Beck D.B.*, Kane-Goldsmith N., Tong Q., Rabanal R.M., Fondevila D., Muñoz P.*, Krüger M., Tischfield J.A. and Vaquero A.*. The Tumor supressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes&Development. Published in Advance March 6, 2013, doi:10.1101/gad.211342.112