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Sirtuins and DNA damage repair: SIRT7 comes to play
Berta N Vazquez1, Joshua K Thackray1, Lourdes Serrano1
1a Rutgers University, Department of Genetics , Human Genetics Institute of New Jersey , Piscataway , NJ , USA.
Abstract:
Aging is characterized by a cumulative loss of genome integrity, which involves chromatin reorganization, transcriptional dysregulation and the accumulation of DNA damage. Sirtuins participate in the protection against these aging processes by promoting genome homeostasis in response to cellular stress. We recently reported that SirT7-/- mice suffer from partial embryonic lethality and a progeroid like phenotype. At the cellular level, SIRT7 depletion results in the impaired repair of DNA double-strand breaks (DSBs), one the most dangerous DNA lesions, leading to genome instability. SIRT7 is recruited to DSBs, where it specifically deacetylates histone H3 at lysine 18 and affects the focal accumulation of the DNA damage response factor 53BP1, thus influencing the efficiency of repair. Here, we integrate our findings with the current knowledge on the mode of action of other sirtuin family members in DNA repair. We emphasize their capacity to regulate chromatin structure as a response to DNA damage within the constraints imposed by cellular status.
Insights
The sirtuin SIRT7 protein is crucial for repairing DNA double-strand breaks (DSBs) and maintaining genome stability during aging. Its absence leads to impaired DNA repair and contributes to aging-related phenotypes.
Area of Science:
- Genetics
- Molecular Biology
- Cellular Biology
Background:
- Aging involves progressive loss of genome integrity, including DNA damage and transcriptional changes.
- Sirtuins are key regulators of cellular stress responses and genome homeostasis.
- SIRT7 deficiency in mice causes embryonic lethality and a progeroid phenotype, indicating its critical role.
Purpose of the Study:
- To investigate the role of Sirtuin 7 (SIRT7) in DNA double-strand break (DSB) repair.
- To elucidate the molecular mechanisms by which SIRT7 influences DNA repair pathways.
- To integrate SIRT7's function within the broader context of sirtuin-mediated DNA repair.
Main Methods:
- Analysis of SIRT7-deficient (SirT7-/-) mice and SIRT7-depleted cells.
- Assessment of DNA double-strand break (DSB) repair efficiency.
- Chromatin immunoprecipitation and Western blotting to study histone modifications and protein recruitment to DSBs.
- Investigation of the interaction between SIRT7, histone H3, and 53BP1.
Main Results:
- SIRT7 depletion impairs the repair of DNA double-strand breaks (DSBs), leading to genome instability.
- SIRT7 is recruited to DSBs and specifically deacetylates histone H3 at lysine 18.
- SIRT7 influences the accumulation of the DNA damage response factor 53BP1 at DSBs, impacting repair efficiency.
Conclusions:
- SIRT7 plays a vital role in maintaining genome integrity by facilitating efficient DSB repair.
- SIRT7's function in DNA repair involves chromatin modification, specifically histone H3 deacetylation.
- Sirtuins, including SIRT7, regulate chromatin structure in response to DNA damage, highlighting their importance in aging and genome stability.