Supplements of vitamin E and C reduce oxidative stress in HIV and produce a trend towards a reduction in viral load. This is worthy of larger clinical trials, especially in HIV-infected persons who cannot afford new combination therapies.

Increased lipid peroxidation induced by reactive oxygen species may play a role in the stimulation of HIV replication. In this study we compared lipid peroxidation indexes and plasma antioxidant micronutrients between 49 nonsmoking HIV-positive patients with no active opportunistic infection (25 asymptomatic and 24 with AIDS) and 15 age-matched seronegative control subjects. Breath-alkane output, plasma lipid peroxides, antioxidant vitamins, and trace elements were measured. Vitamin C (40.7 +/- 3.02 compared with 75.7 +/- 4.3 mumol/L, P < 0.005), alpha-tocopherol (22.52 +/- 1.18 compared with 26.61 +/- 2.60 mumol/L, P < 0.05), beta-carotene (0.23 +/- 0.04 compared with 0.38 +/- 0.04 mumol/L, P < 0.05), and selenium (0.37 +/- 0.05 compared with 0.85 +/- 0.09 mumol/L, P < 0.005) concentrations were significantly lower in the HIV-positive patients. Lipid peroxides (50.7 +/- 8.2 compared with 4.5 +/- 0.8 mumol/L, P < 0.005), breath pentane (9.05 +/- 1.23 compared with 6.06 +/- 0.56 pmol.kg-1.min-1, P < 0.05), and ethane output (28.1 +/- 3.41 compared with 11.42 +/- 0.55 pmol.kg-1.min-1, P < 0.05) were significantly higher in the HIV-positive patients. These results showed an increase in oxidative stress and a weakened antioxidant defense system in HIV-positive patients. Whether supplementation of antioxidant vitamins will reduce this oxidative stress is still unknown.

p53 mediates DNA damage-induced cell-cycle arrest, apoptosis, or senescence, and it is controlled by Mdm2, which mainly ubiquitinates p53 in the nucleus and promotes p53 nuclear export and degradation. By searching for the kinases responsible for Mdm2 S163 phosphorylation under genotoxic stress, we identified S6K1 as a multifaceted regulator of Mdm2. DNA damage activates mTOR-S6K1 through p38a MAPK. The activated S6K1 forms a tighter complex with Mdm2, inhibits Mdm2-mediated p53 ubiquitination, and promotes p53 induction, in addition to phosphorylating Mdm2 on S163. Deactivation of mTOR-S6K1 signalling leads to Mdm2 nuclear translocation, which is facilitated by S163 phosphorylation, a reduction in p53 induction, and an alteration in p53-dependent cell death. These findings thus establish mTOR-S6K1 as a novel regulator of p53 in DNA damage response and likely in tumorigenesis. S6K1-Mdm2 interaction presents a route for cells to incorporate the metabolic/energy cues into DNA damage response and links the aging-controlling Mdm2-p53 and mTOR-S6K pathways.

DNA damage triggers Atm-and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events. Cell Death and Differentiation (2011) 18, 5-15; doi:10.1038/cdd.2010; published online 27 August 2010 DNA damage can be caused by exogenous or endogenous factors such as ionizing radiation (IR), chemotherapeutic drugs, and stalled replication forks. 1 It is believed that various DNA lesions are eventually converted to double-stranded breaks (DSBs) and/or single-stranded DNA (ssDNA or SSBs), where sensors, mediators, transducers, and effectors assemble to form nuclear foci, which function as centers of signal propagation. At the core of the signaling network are PI-3 kinase-like kinases (PIKKs), including Atm, Atr and DNA-PKcs. 2 Atm is mainly activated by DSBs, whereas Atr responds to various DNA lesions. 3 Atm and Atr are recruited to the nuclear foci by the MRN (Mre11-Rad50-NBS) complex and ATRIP, respectively, 4,5 where they phosphorylate proteins such as p53, Chk1, Chk2, and H2AX, to activate cell cycle checkpoints and/or induce apoptosis. 6 Phosphorylation of Chk1 and Chk2 by Atr and Atm is facilitated by a group of nuclear foci proteins called mediators, for example, Brca1, TopBP1, and 53BP1. Furthermore, the nuclear foci also function as repair centers. 7 DSB repair is believed to involve an Atm to Atr switch. 8,9 Atm is first recruited to DSBs and ssDNA is later generated by resection of the DNA ends, where Atr can be assembled and activated. Thus, there exists a complex functional interaction between these two PIKKs. 10 Although several proteins have been reported to activate Atm or Atr, 11,12 the initial activation of Atm/Atr and the regulation of their activities in the process of DNA repair are poorly understood. 13,14 The c-Abl proto-oncogene encodes a non-receptor tyrosine kinase that is essential for perinatal survival in ...