Division of Cellular Senescence, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan.
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan.
Commun Biol. 2022 Dec 28;5(1):1420. doi: 10.1038/s42003-022-04369-7.
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.
致癌刺激引起的细胞衰老与衰老相关分泌表型 (SASP) 有关，通过 SASP 促进各种与年龄相关的病理发生。SASP 是由细胞质核酸传感器的激活介导的。然而，衰老细胞中核苷酸配体积累的分子机制尚不清楚。在这项研究中，我们揭示了 RNaseH2A 的表达受 E2F 转录因子调控，其在细胞衰老过程中减少。残留的 rNMP 导致基因组 DNA 片段化和细胞质核酸传感器的异常激活，从而引发衰老细胞中随后的 SASP 因子基因表达。此外，在老年小鼠组织和 Werner 综合征患者的细胞中，RNaseH2A 的表达显著降低。此外，使用生长素诱导的降解系统降解 RNaseH2A 会导致核苷酸配体的积累和某些致瘤性 SASP 样因子的诱导，从而促进结直肠癌细胞的转移特性。我们的结果表明，RNaseH2A 的下调通过核苷酸配体的积累引发 SASP，这可能是衰老、早衰和癌细胞的病理特征的原因。
