title: RRM2B suppresses activation of the oxidative stress pathway and is up-regulated by p53 during senescence.
abstract: RRM2B is the DNA damage-inducible small subunit of ribonucleotide reductase, the rate-limiting enzyme in de novo deoxyribonucleoside triphosphate synthesis. Although RRM2B is implicated in DNA repair and the maintenance of mitochondrial DNA content, the regulation and function of RRM2B in senescence have not been previously established. Here, we show that RRM2B is highly induced in a p53-dependent manner during senescence in primary human fibroblast IMR90 cells and is expressed at higher levels in senescent precancerous human prostatic intraepithelial neoplasm lesions compared to adjacent normal prostate glands. Paradoxically, silencing RRM2B expression leads to an increase in the level of reactive oxygen species, mitochondrial membrane depolarization, and premature senescence in a p38MAPK- and p53-dependent manner in young fibroblasts. Consistently, induction of senescence is accelerated in Rrm2b deficient mouse embryo fibroblasts. Our data demonstrate that RRM2B is induced by stress signals prior to the onset of senescence and prevents premature oxidative stress-induced senescence.
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. mkuo@coh.org
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Kuo
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Sy
authors.forename: Lijun
authors.initials: L
authors.lastname: Xue
authors.forename: Martin
authors.initials: M
authors.lastname: Chi
authors.forename: Michelle T-C
authors.initials: MT
authors.lastname: Lee
authors.forename: Terence
authors.initials: T
authors.lastname: Yen
authors.forename: Mei-Iok
authors.initials: MI
authors.lastname: Chiang
authors.forename: Lufen
authors.initials: L
authors.lastname: Chang
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016922:Cellular Senescence; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; D048051:p38 Mitogen-Activated Protein Kinases