H3K4me2 Regulates Recovery of Cell Function Following Repair of DNA Damage

Researchers here investigate the regulation of mechanisms governing restoration of cell function following DNA repair. They find that H3K4me2, an epigenetic modification of histone H3, is important, and suggest that this could be a target for slowing the impact of DNA damage on the progression of aging. It is interesting to read this work in the context of data from last year that indicates detrimental epigenetic change with age may be an unfortunate side-effect of the repair process for double-strand breaks in DNA. It seems likely that, in the years ahead, an arm of the longevity industry will arise focused on manipulating DNA repair and surrounding mechanisms via known points of regulation such as histone H3.

The genome in every human cell is damaged on a daily basis, for example in the skin by UV radiation from the sun. Damage to the DNA causes diseases such as cancer, influences development, and accelerates aging. Congenital malfunctions in DNA repair can lead to extremely accelerated aging in rare hereditary diseases. Therefore, preservation and reconstruction processes are particularly important to ensure development and to maintain tissue function. DNA is rolled up into structures called chromatin, wound around the histone packaging proteins like cables on cable drums. This packaging is regulated by methyl groups. Various proteins are responsible for placing methyl groups on histones or removing them. The number of groups on the packaging proteins affects the activity of genes and thus the protein production of the cell.

In experiments with nematodes, the research team showed that after repairing damaged DNA, two methyl groups were increasingly found on the DNA packages. Furthermore, they found that errors in placing these two methyl groups on the histones (H3K4me2) accelerated the damage-induced aging process, while increased position of this histone alteration prolongs the lifespan after DNA damage. By controlling the proteins that either set or remove these methyl groups, the resistance to DNA damage - and thus the aging process of the animals - could be influenced.

Further analysis of the role of these two methyl groups showed that the enrichment of H3K4 after genome damage with two methyl groups supports the cells in restoring the balance after DNA damage. "Now that we know the exact changes in chromatin, we can use this to precisely limit the consequences of DNA damage. I hope that these findings will enable us to develop therapies for hereditary diseases characterized by developmental disorders and premature aging. Due to the fundamental importance of DNA damage in the aging process, such approaches could also counteract normal aging and prevent age-related diseases."

Link: https://portal.uni-koeln.de/en/universitaet/aktuell/press-releases/single-news/forschungsteam-entdeckt-mechanismus-der-die-zellfunktion-nach-genomschaeden-wiederherstellt

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