Broad repression of DNA repair genes in senescent cells identified by integration of transcriptomic data

Abstract

Cellular senescence plays a significant role in tissue aging. Senescent cells, which resist apoptosis while remaining metabolically active, generate endogenous DNA-damaging agents, primarily reactive oxygen species. Efficient DNA repair is therefore crucial in these cells, especially when they undergo senescence escape, resuming DNA replication and cellular proliferation. To investigate whether senescent cell transcriptomes reflect adequate DNA repair capacity, we conducted a comprehensive meta-analysis of 60 transcriptomic datasets comparing senescent to proliferating cells. Our analysis revealed a striking downregulation of genes encoding essential components across DNA repair pathways in senescent cells. This includes pathways active in different cell cycle phases such as nucleotide excision repair, base excision repair, nonhomologous end joining and homologous recombination repair of double-strand breaks, mismatch repair and interstrand crosslink repair. The downregulation observed suggests a significant accumulation of DNA lesions. Experimental monitoring of DNA repair readouts in cells that underwent radiation-induced senescence supported this conclusion. This phenomenon was consistent across various senescence triggers and was also observed in primary cell lines from aging individuals. These findings highlight the potential of senescent cells as ‘ticking bombs’ in aging-related diseases and tumors recurring following therapy-induced senescence.