Rescuing accelerated DNA damage models by targeting the aging-induced inflammation process
2Obstetrics and Gynecology, Shaare Zedec Medical Center, Israel
To further elucidate the relationship between genomic instability and aging we developed accelerated DNA damage models such as the Ataxia Telangiectasia (A-T) and Bloom Syndrome (BS) in the African Turquoise Killifish. Both proteins are activated by damage to the DNA, A-T is a translation dependent sensor of double strand breaks (DSB), while BS is a replication dependent helicase facilitating unwinding for DNA digestion and DSB repair.
Mouse models do not recapitulate the full human phenotype, A-T mouse models do not show signs of neurodegeneration, and the BS model suffers from early embryonic lethality of mutant homozygotes. Partially because of their longer telomeres and lifespan compared to the Killifish.
Aging is associated with genomic instability, and induction of genomic instability can accelerate aspect of the aging process. Here we generated and presented 2 genetic models of DNA damage repair, ATM and Blm.
We show that our African Turquoise Killifish models recapitulate phenotypes of the human syndromes, such as infertility and aberrant DNA damage response.
We aim to further investigate the involvement of Interferon-Stimulated Genes (ISG) in these models with RNA sequencing, and genetic models of the key ISG regulators cGAS and STING. Answers to these questions could shed light on the relationship between accumulation of damage to the DNA and the aging process.