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- Title
RNaseH2A downregulation drives inflammatory gene expression via genomic DNA fragmentation in senescent and cancer cells.
- Authors
Sugawara, Sho; Okada, Ryo; Loo, Tze Mun; Tanaka, Hisamichi; Miyata, Kenichi; Chiba, Masatomo; Kawasaki, Hiroko; Katoh, Kaoru; Kaji, Shizuo; Maezawa, Yoshiro; Yokote, Koutaro; Nakayama, Mizuho; Oshima, Masanobu; Nagao, Koji; Obuse, Chikashi; Nagayama, Satoshi; Takubo, Keiyo; Nakanishi, Akira; Kanemaki, Masato T.; Hara, Eiji
- Abstract
Cellular senescence caused by oncogenic stimuli is associated with the development of various age-related pathologies through the senescence-associated secretory phenotype (SASP). SASP is mediated by the activation of cytoplasmic nucleic acid sensors. However, the molecular mechanism underlying the accumulation of nucleotide ligands in senescent cells is unclear. In this study, we revealed that the expression of RNaseH2A, which removes ribonucleoside monophosphates (rNMPs) from the genome, is regulated by E2F transcription factors, and it decreases during cellular senescence. Residual rNMPs cause genomic DNA fragmentation and aberrant activation of cytoplasmic nucleic acid sensors, thereby provoking subsequent SASP factor gene expression in senescent cells. In addition, RNaseH2A expression was significantly decreased in aged mouse tissues and cells from individuals with Werner syndrome. Furthermore, RNaseH2A degradation using the auxin-inducible degron system induced the accumulation of nucleotide ligands and induction of certain tumourigenic SASP-like factors, promoting the metastatic properties of colorectal cancer cells. Our results indicate that RNaseH2A downregulation provokes SASP through nucleotide ligand accumulation, which likely contributes to the pathological features of senescent, progeroid, and cancer cells. The levels of catalytic subunit of the RNaseH2 enzyme, RNAseH2A, decrease during senescence promoting nucleotide accumulation and a senescence-associated secretory phenotype.
- Subjects
GENE expression; CANCER cells; CELLULAR aging; DNA; NUCLEIC acids; DOWNREGULATION
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-04369-7