TY - JOUR
T1 - RNaseH2A downregulation drives inflammatory gene expression via genomic DNA fragmentation in senescent and cancer cells
AU - Sugawara, Sho
AU - Okada, Ryo
AU - Loo, Tze Mun
AU - Tanaka, Hisamichi
AU - Miyata, Kenichi
AU - Chiba, Masatomo
AU - Kawasaki, Hiroko
AU - Katoh, Kaoru
AU - Kaji, Shizuo
AU - Maezawa, Yoshiro
AU - Yokote, Koutaro
AU - Nakayama, Mizuho
AU - Oshima, Masanobu
AU - Nagao, Koji
AU - Obuse, Chikashi
AU - Nagayama, Satoshi
AU - Takubo, Keiyo
AU - Nakanishi, Akira
AU - Kanemaki, Masato T.
AU - Hara, Eiji
AU - Takahashi, Akiko
N1 - Funding Information:
We thank the members of the Takahashi laboratory for their helpful support during the preparation of this manuscript. This work was supported in part by grants from the Japan Agency of Medical Research and Development (AMED) under grant number 19gm6110023h0001; the Japan Science and Technology Agency (JST)-PRESTO under grant number JPMJPR17H7; JST-Moonshot R&D under grant number JPMJPS2022; Japan Society for the Promotion of Science (JSPS) under grant number (No. 17K19618, 19H03507, 17H06413, 17H06417, 18J10977, 21J01769, 22H02907 and 22K07198); the Naito Foundation, the Uehara Memorial Foundation and the Foundation for Promotion of Cancer Science.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-022-04369-7
DO - 10.1038/s42003-022-04369-7
M3 - Article
C2 - 36577784
AN - SCOPUS:85145050638
SN - 2399-3642
VL - 5
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 1420
ER -
