title: Oxidative stress preferentially induces a subtype of micronuclei and mediates the genomic instability caused by p53 dysfunction.
abstract: Reactive oxygen species (ROS) are known to cause many types of DNA lesions that could be converted into cancer-promoting genetic alterations. Evidence showed that tumor suppressor p53 plays an important role in regulating the generation of cellular ROS, either by reducing oxidative stress under physiological and mildly stressed conditions, or by promoting oxidative stress under highly stressed conditions. In this report we characterized the effect of oxidative stress on the induction of micronuclei, especially the subclass marked by pan-staining of γ-H2AX or MN-γ-H2AX (+). We found that MN-γ-H2AX (+) were more responsive to hydrogen peroxide (H2O2) than the MN-γ-H2AX (−). In human and mouse cells that are deficient in p53, the frequency of MN-γ-H2AX (+) is significantly elevated, but can be attenuated by antioxidant N-acetylcysteine (NAC). Depletion of p53-regulated antioxidant gene SESN1 by RNA interference also resulted in an elevation of MN-γ-H2AX (+). Furthermore, we found that in cells that were depleted of p400 by RNAi, and therefore were experiencing increased ROS, the frequency of MN-γ-H2AX (+), but not that of MN-γ-H2AX (−), was significantly induced. We further demonstrated that the induction of MN-γ-H2AX (+) by replication stress can also be attenuated by NAC, and that H2O2 also leads to increased phosphorylation of Chk1 and Rad17 that mimics replication stress, suggesting that replication stress and oxidative stress are intertwined and may reinforce each other in driving genomic instability. Our findings illustrate the importance of p53-regulated redox level in the maintenance of genomic stability.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.forename: Wenxing
authors.initials: W
authors.lastname: Wang
authors.forename: Haiyang
authors.initials: H
authors.lastname: Guo
authors.forename: Zhaoliang
authors.initials: Z
authors.lastname: Sun
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wei
authors.forename: Xiyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhaojian
authors.initials: Z
authors.lastname: Liu
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D042822:Genomic Instability / Q000187:drug effects / Q000235:genetics*; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide