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.

HSP90 inhibitors in the context of heat shock and the unfolded protein response: effects on a primary canine pulmonary adenocarcinoma cell line*

“…Survivin follows a similar pattern, while XIAP is quite reduced in the combination setting. Claspin, a cell-cycle checkpoint regulator, also follows the previous patterns resulting ultimately in low levels, which may be due to its degradation during apoptosis [54], but another checkpoint protein, RAD17 [55], increases in its phospho-state, which may be related to the stress response [56]. Of the chaperones in this panel with anti-apoptotic properties [57, 58], the clusterin expression pattern again resembles XIAP and claspin, while other chaperones (HSP32/HMOX1 and related HMOX2 [59], HSP27, and HSP70) show increased expression during UPR stress, greater expression with drug treatment, and maintain relatively high levels with the combination of stress and drug treatment.…”

p53 pathway determines the cellular response to alcohol-induced DNA damage in MCF-7 breast cancer cells

“…These data suggest that alcohol enhances DNA damage in cells with p53 mutation/inactivation. The mechanism underlying enhanced alcohol-induced DNA damage in MCF-7/sip53 cells may result from the decrease of anti-oxidant and DNA repair genes regulated by p53, such as SESN1 (an anti-oxidant gene) and DNA polymerase-β (a DNA repair gene involved in new strand synthesis) [56, 57]. In context with the notion that p53 mutations are associated with genomic instability, enhanced alcohol-induced DNA damage in these cells could form a vicious feedback loop that may promote malignant transformation.…”

Teratozoospermia and karyopathological abnormalities of blood cells in human granulocytic anaplasmosis depending on polymorphism of GSTM1 gene of glutathion-S-transferase

“…Не исключено, что сопряженные кариопатологические изменения в клетках крови и тератозооспермия обусловлены наличием эндогенных факторов, повреждающих ДНК. Непропорциональная генерация реактивных форм кислорода (ROS), включающих супероксиданион радикал, пероксид водорода, гидроксильные радикалы, а также секреция реактивных форм оксида азота (RNS) иммуноцитами при инфекционных заболеваниях вызывают повреждение клеточных макромолекул, включая ДНК и ферменты [11,[13][14][15].…”

“…Это позволяет предположить, что цитогенетический эффект анаплазм может быть обусловлен окислительным стрессом, вызванным внедрением паразита в организм [13,15]. Под влиянием ROS в клетках происходит разрушение тубулиновых волокон ахроматинового аппарата деления, что способствует аномальному расхождению хромосом в митозе, приводящему к формированию микроядер [8].…”