Restricting the level of the proteins essential for the regulation of the initiation step of replication extends the chronological lifespan and reproductive potential in budding yeast

Abstract

Aging is defined as a progressive decline in physiological integrity, leading to impaired biological function, including fertility, and rising vulnerability to death. Disorders of DNA replication often lead to replication stress and are identified as factors influencing the aging rate. In this study, we aimed to reveal how the cells that lost strict control of the formation of crucial for replication initiation a pre-initiation complex impact the cells' physiology and aging. As strains with the lower pre-IC control (lowPICC) we used, Saccharomyces cerevisiae heterozygous strains having only one functional copy of genes, encoding essential replication proteins such as Cdc6, Dbf4, Sld3, Sld7, Sld2, and Mcm10. The lowPICC strains exhibited a significant reduction in the respective genes' mRNA levels, causing cell cycle aberrations and doubling time extensions. Additionally, the reduced expression of the lowPICC genes led to an aberrant DNA damage response, affected cellular and mitochondrial DNA content, extended the lifespan of post-mitotic cells, and increased the yeast's reproductive potential. Importantly, we also demonstrated a strong negative correlation between the content of cellular macromolecules (RNA, proteins, lipids, polysaccharides) and aging. The data presented here will likely contribute to the future development of therapies for treating various human diseases.