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

Area of Science:

• Cellular and Molecular Biology
• Genetics and Epigenetics
• Aging Research

Background:

• Cellular senescence is a key driver of aging and contributes to age-related diseases.
• Senescent cells resist apoptosis but remain metabolically active, producing DNA-damaging reactive oxygen species.
• Efficient DNA repair is critical for senescent cells, particularly during senescence escape and proliferation.

Purpose of the Study:

• To investigate the DNA repair capacity of senescent cells by analyzing their transcriptomes.
• To determine if senescent cell transcriptomes reflect a compromised DNA repair machinery.
• To assess the implications of impaired DNA repair in senescence for aging and disease.

Main Methods:

• A comprehensive meta-analysis of 60 transcriptomic datasets comparing senescent and proliferating cells.
• Analysis of gene expression across various DNA repair pathways, including those for nucleotide excision repair, base excision repair, nonhomologous end joining, homologous recombination repair, mismatch repair, and interstrand crosslink repair.
• Experimental validation using radiation-induced senescence models and primary cell lines from aging individuals.

Main Results:

• Significant downregulation of genes essential for multiple DNA repair pathways was observed in senescent cells.
• This downregulation suggests a substantial accumulation of DNA lesions within senescent cells.
• Impaired DNA repair capacity was consistent across different senescence triggers and in aged primary cells.

Conclusions:

• Senescent cells possess a compromised DNA repair system, leading to DNA lesion accumulation.
• This impaired repair mechanism may position senescent cells as 'ticking bombs' in aging-related diseases and cancer.
• Therapy-induced senescence may lead to tumor recurrence due to senescent cells' reduced DNA repair efficiency.