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Epigenetic regulation of protein homeostasis following DNA damage

Recent study identifies critical regulator of protein biosynthesis recovery and homeostasis required for Longevity.

Unresolved DNA damage caused by intrinsic and environmental factors accumulates during a cell’s lifetime. This accumulation of damaged DNA over time accelerates aging – also known as the DNA damage theory of aging [1, 2]. Indeed, numerous premature aging syndromes have been linked to genomic instability, suggesting a role for DNA damage accumulation in the development of age-related diseases [3]. However, the molecular mechanisms underlying the role of DNA damage responses in Longevity remain unclear.

Longevity.Technology: Scientists from the Institute for Genome Stability in Ageing and Disease, University of Cologne (Germany) identified a role for histone 3 lysine 4 dimethylation (H3K4me2) in orchestrating the recovery of protein biosynthesis and homeostasis required for developmental growth and Longevity after DNA damage. The study was led by Professor Björn Schumacher and was published in October 2020 in the journal Nature Structural & Molecular Biology [4].

The central role of DNA damage in cancer has been known for years. Recent evidence suggests that DNA damage accumulation can also impair developmental processes and accelerate aging. Notably, blocked gene transcription due to unrepaired DNA damage lesions can lead to developmental defects and premature aging in humans.

 


 

 

“We have uncovered mechanisms through which Longevity assurance pathways respond to DNA damage accumulation and antagonize the detrimental consequences of increasing levels of DNA damage with aging…”

 


 

Schumacher’s research team showed in the nematode Caenorhabditis elegans that ultraviolet (UV) irradiation, one of the most common environmental factors causing DNA damage, led to developmental arrest and increased H3K4me2 levels.

“It remains particularly challenging to understand the mechanisms through which genome instability impacts the pathobiology of aging, says Schumacher [5]. “We have established the C. elegans system to investigate how DNA damage impacts tissue aging and how multicellular organisms respond to increasing levels of genome instability with aging.”

Epigenetic regulation of protein biosynthesis recovery upon DNA damage
Picture of C. elegans with H3K4me2 in green, H3K4me3 in red, DAPI in blue. Source: Dr. Siyao Wang

First Longevity

To assess the role of H3K4me2 in the developmental defects following UV irradiation, the scientists generated mutant worms lacking H3K4me2. Interestingly, the lack of H3K4me2 worsened developmental defects and accelerated aging in UV-irradiated worms. Importantly, genetic depletion of H3K4 demethylases and subsequent increase in H3K4me2 levels protected from developmental retardation and extended lifespan after UV-induced DNA damage.

The scientists also demonstrated that in response to DNA damage, H3K4me2 induces the expression of genes regulating pivotal cellular functions, including ribosome biogenesis, RNA transport, splicing, and protein homeostasis. This H3K4me2-mediated gene expression reprogramming restores protein biosynthesis and homeostasis required for tissue functionality and survival following DNA damage repair.

Increasing evidence suggests an important role of DNA damage in the regulation of Longevity, possibly by affecting cell function and causing stem cell depletion. This study pinpoints H3K4me2 as a critical epigenetic mechanism maintaining protein homeostasis required for Longevity after DNA damage. Although H3K4me2 is a highly conserved epigenetic mark, validation of these findings in other preclinical models and humans is required before epigenetic modifiers can be targeted to extend healthy life.

“We have uncovered mechanisms through which Longevity assurance pathways respond to DNA damage accumulation and antagonize the detrimental consequences of increasing levels of DNA damage with aging,” says Schumacher [5]. “Our long-term goals are gaining a deeper understanding of genome maintenance and Longevity assurance pathways and to develop novel intervention strategies to combat aging-associated diseases and genetic predispositions to accelerated aging and cancer development.”

[1] https://pubmed.ncbi.nlm.nih.gov/21600302/
[2] https://royalsocietypublishing.org/doi/10.1098/rsob.190168
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588127/
[4] https://www.nature.com/articles/s41594-020-00513-1#Bib1
[5] https://bit.ly/3oeqYEx

First Longevity
Images courtesy of CECAD Research Center / CECAD Forschungszentrum
Christos Evangelou
Since the completion of his undergraduate and doctoral studies in Molecular Biosciences, Christos has been working in the medical communications industry, driven by his passion for communicating sciences. Apart from helping researchers to publish their studies, Christos writes articles related to sciences and medicine.
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