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Inhibiting DREAM for Enhanced DNA Damage Repair

This approach is effective in worms, human cells, and mice.Β 

Abstract DNAAbstract DNA

In a new study published in Nature Structural and Molecular Biology, researchers have demonstrated that by manipulating the DREAM protein complex, a major regulator of DNA damage response, it might be possible to alter the number of DNA mutations accumulated with age [1].

Mutations and DREAMs

DNA mutations spontaneously occur in both germ-line (reproductive) cells and somatic cells. Although all types of cells employ a DNA repair system, the mutation rate of germ-line cells is much lower than that of somatic cells, possibly owing to a more efficient DNA damage response [2].

From an evolutionary point of view, it makes sense to limit the number of mutations in the germ-line cells to ensure the integrity of the genome passed on to future generations. Somatic mutations, on the other hand, are not inherited and therefore have less pressure to be eliminated.

With age the mutation rate in somatic cells increases, which contributes to the development of age-associated diseases such as cancer. Genomic instability is one of the hallmarks of aging. Ways to target this process are being explored to delay aging.

DREAM is an evolutionarily conserved protein complex that regulates gene expression in a cell cycle-dependent manner. It is formed by Dp/Retinoblastoma(Rb)-like/E2F and the MuvB subcomplexes, although the exact composition varies across species.

DREAM is known for repressing certain genes in the G0 phase (resting or quiescent) of the cell cycle. Mutations in the genes comprising the DREAM complex were shown to make somatic cells more similar to germ-line cells.

Therefore, the authors of this study explored the idea that DREAM is involved in the regulation of the DNA mutation rate in somatic cells of different species.

Daytime is not for DREAMingΒ 

First, the researchers surveyed DNA damage response and repair (DDR) genes in the worm C.elegans and found that many of them are regulated by the DREAM complex.

Next, the scientists used UV irradiation to induce DNA mutations in the worm larvae. They showed that animals with mutations in DREAM complex components were more resilient to UV-caused DNA lesions than wild-type animals, as their development was not delayed.

The researchers then UV-irradiated the worms on the first day of adulthood to simulate aging-associated DNA damage. These experiments also showed that mutations in DREAM complex components made the animals more resilient to DNA damage, as they outlived the wild-type worms.

In the next set of experiments, the researchers decided to focus on a specific component of the DREAM complex, the LIN-52 gene, due to the strong UV resistance demonstrated by the worms with mutations in this gene.

DREAM suppresses DNA repair

By quantifying a specific type of DNA lesions caused by UV irradiation in both larvae and adult worms, the researchers showed that LIN-52 mutations enhanced DNA repair. This effect was specific to the somatic cells of the worms.

The researchers then performed RNA sequencing of LIN-52 mutants and control animals. As expected, many of the upregulated genes in LIN-52 mutants were those involved in DNA-repair mechanisms. The proteomic analysis confirmed these results.

Following qPCR analysis and comparing the results obtained in this study with the previously published data, the researchers discovered that not only LIN-52 but also other DREAM complex genes directly bind and repress multiple components of DNA repair pathways.

By comparing the expression pattern of LIN-52 mutants and germ-line cells, the researchers showed that they are very similar. This suggests that DREAM suppresses genes in the somatic cells that are usually expressed in germ-line cells, i.e. those that are necessary for DNA damage repair.

Beyond UV and worms

The researchers then induced DNA damage in LIN-52 mutant worms with different types of insults: ionizing radiation, alkylation damage, and cisplatin, an antitumor drug known to cause DNA interstrand crosslinks. The LIN-52 mutants proved resistant to all these different types of DNA damage.

A set of experiments in human cells showed that, just like in worms, the mammalian DREAM complex directly binds DNA repair genes, while its inhibition with pharmacological agents boosts the cells’ resistance to DNA damage induced by UV or alkylation.

Finally, DREAM inhibition with a pharmacological agent in progeroid mice (with mutations in Errc1, a DNA damage repair gene) reduced DNA damage in the retina and decreased photoreceptor loss.

Abstract excerpt

DREAM mutants confer resistance to a wide range of DNA-damage types during development and aging. Similarly, inhibition of the DREAM complex in human cells boosts DNA-repair gene expression and resistance to distinct DNA-damage types. DREAM inhibition leads to decreased DNA damage and prevents photoreceptor loss in progeroid Ercc1βˆ’/βˆ’ mice. We show that the DREAM complex transcriptionally represses essentially all DNA-repair systems and thus operates as a highly conserved master regulator of the somatic limitation of DNA-repair capacities.

Conclusion

This comprehensive study has shown that it is possible to enhance the DNA damage repair capacity of somatic cells not only in worms but also mice and human cells by inhibiting a specific protein complex. Although the cellular and animal models used in this study don’t entirely replicate what happens in human aging, this research provides evidence that by manipulating certain genes in certain tissues, it is possible to reverse age-associated damage accumulation.

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Literature

[1] Bujarrabal-Dueso A, Sendtner G, Meyer DH, Chatzinikolaou G, Stratigi K, Garinis GA et al. The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities. Nat Struct Mol Biol 2023. doi:10.1038/s41594-023-00942-8.

[2] Ohno M. Spontaneous de novo germline mutations in humans and mice: rates, spectra, causes and consequences. Genes Genet Syst 2019; 94: 13–22.

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About the author
Larisa Sheloukhova

Larisa Sheloukhova

Larisa is a recent graduate from Okinawa Institute of Science and Technology located in one of the blue zones. She is a neurobiologist by training, a health and longevity advocate, and a person with a rare disease. She believes that by studying hereditary diseases it’s possible to understand aging better and vice versa. In addition to writing for LEAF, she continues doing research in glial biology and runs an evidence-based blog about her disease. Larisa enjoys pole fitness, belly dancing, and Okinawan pristine beaches.
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