Niacin, poly(ADP-ribose) polymerase-1 and genomic stability

Nicotinic acid (NA) and nicotinamide (NAM), commonly called niacin, are the dietary precursors for NAD+ (nicotinamide adenine dinucleotide), which is required for DNA synthesis, as well as for the activity of the enzyme poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) for which NAD+ is the sole substrate. The enzyme PARP-1 is highly activated by DNA strand breaks during the cellular genotoxic stress response, is involved in base excision repair, plays a role in p53 expression and activation, and hence, is thought to be important for genomic stability. In this review, first the absorption, metabolism of niacin to NAD+, as well as the assessment of niacin status are discussed. Since NAD+ is important for PARP-1 activity, various aspects of PARP-1 in relation to DNA synthesis and repair, and regulation of gene expression are addressed. This is followed by a discussion on interactions between dietary methyl donor deficiency, niacin status, PARP-1 activity and genomic stability. In vitro studies show that PARP-1 function is impaired and genomic stability decreased when cells are either depleted from NAD+ or incubated with high concentrations of NAM which is a PARP-1 inhibitor. In vitro as well as animal studies indicate that niacin deficiency increases genomic instability especially in combination with genotoxic and oxidative stress. Niacin deficiency may also increase the risk for certain tumors. Preliminary data suggest that niacin supplementation may protect against UV-induced tumors of the skin in mice, but data on similar preventive effects in humans are not available. NAM has been shown in vitro to have an antioxidant activity comparable to that of ascorbic acid. Data on niacin status and genomic stability in vivo in humans are limited and yield ambiguous results. Therefore, no firm conclusions with respect to optimal niacin intake are possible. As a consequence of oral niacin supplementation, however, NAM levels in the body may increase, which may result in inhibition of PARP-1 and increased genomic instability. More studies are needed to define an optimal level of niacin nutriture in relation to genomic stability and tumorigenesis. © 2001 Elsevier Science B.V. Chemicals/CAS: DNA, 9007-49-2; Niacin, 59-67-6; Poly(ADP-ribose) Polymerases, EC 2.4.2.3

Nicotinic acid supplementation: effects on niacin status, cytogenetic damage, and poly(ADP-ribosylation) in lymphocytes of smokers.

Department of Health Risk Analysis and Toxicology, Universiteit Maastricht, The Netherlands.As a substrate for poly(ADP-ribose) polymerase (PARP; EC, 2.4.2.30), an enzyme that is activated by DNA strand breaks and is thought to facilitate efficient DNA repair, NAD+ and its precursor nicotinic acid (niacin) are involved in the cellular defense against DNA damage by genotoxic compounds. In this study, the effect of nicotinic acid supplementation on cytogenetic damage and poly(ADP-ribosylation) was evaluated in a human population that is continuously exposed to genotoxic agents, e.g., smokers. By use of a placebo-controlled intervention design, 21 healthy smokers received supplementary nicotinic acid at 0-100 mg/day for 14 weeks. An increased niacin status, as assessed from blood nicotinamide concentrations and lymphocyte NAD+ concentrations, was observed in groups supplemented with 50 and 100 mg/day. This effect was most pronounced in subjects with lower initial NAD+ levels. An increased niacin status did not result in decreased hypoxanthine guanine phosphoribosyltransferase variant frequencies and micronuclei induction in peripheral blood lymphocytes (PBLs). Sister chromatid exchanges in PBLs, however, were increased after supplementation with nicotinic acid. This increase was positively associated with the daily dose of nicotinic acid. No effects of nicotinic acid supplementation were found for ex vivo (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene-induced poly(ADP-ribosylation), although the small number of samples that could be analyzed (n = 12) does not allow firm conclusions. Because no evidence was found for a decrease in cigarette smoke-induced cytogenetic damage in PBLs of smokers after nicotinic acid supplementation of up to 100 mg/day, it is concluded that supplemental niacin does not contribute to a reduced genetic risk in healthy smokers.Publication Types: Clinical Trial Randomized Controlled Tria

An hybrid approach for the parallelization of a block iterative algorithm

The Cimmino method is a row projection method in which the original linear system is divided into subsystems. At every iteration, it computes one projection per subsystem and uses these projections to construct an approximation to the solution of the linear system. The usual parallelization strategy in block algorithms is to distribute the different blocks on the available processors. In this paper, we follow another approach where we do not perform explicitly this block distribution to processors within the code, but let the multi-frontal sparse solver MUMPS handle the data distribution and parallelism. The data coming from the subsystems defined by the block partition in the Block Cimmino method are gathered in an unique block diagonal sparse matrix which is analysed, distributed and factorized in parallel by MUMPS. Our target is to define a methodology for parallelism based only on the functionalities provided by general sparse solver libraries and how efficient this way of doing can b

An hybrid approach for the parallelization of a block iterative algorithm

The Cimmino method is a row projection method in which the original linear system is divided into subsystems. At every iteration, it computes one projection per subsystem and uses these projections to construct an approximation to the solution of the linear system. The usual parallelization strategy in block algorithms is to distribute the different blocks on the available processors. In this paper, we follow another approach where we do not perform explicitly this block distribution to processors within the code, but let the multi-frontal sparse solver MUMPS handle the data distribution and parallelism. The data coming from the subsystems defined by the block partition in the Block Cimmino method are gathered in an unique block diagonal sparse matrix which is analysed, distributed and factorized in parallel by MUMPS. Our target is to define a methodology for parallelism based only on the functionalities provided by general sparse solver libraries and how efficient this way of doing can be

Identification of a novel ATM inhibitor with cancer cell specific radiosensitization activity

Treatment of advanced head and neck squamous cell carcinoma (HNSCC) is plagued by low survival and high recurrence rates, despite multimodal therapies. Presently, cisplatin or cetuximab is used in combination with radiotherapy which has resulted in minor survival benefits but increased severe toxicities relative to RT alone. This underscores the urgent need for improved tumor-specific radiosensitizers for better control with lower toxicities. In a small molecule screen targeting kinases, performed on three HNSCC cell lines, we identified GSK635416A as a novel radiosensitizer. The extent of radiosensitization by GSK635416A outperformed the radiosensitization observed with cisplatin and cetuximab in our models, while exhibiting virtually no cytotoxicity in the absence of radiation and in normal fibroblast cells. Radiation induced phosphorylation of ATM was inhibited by GSK635416A. GSK63541A increased DNA double strand breaks after radiation and GSK63541A mediated radiosensitization was lacking in ATM-mutated cells thereby further supporting the ATM inhibiting properties of GSK63541A. As a novel ATM inhibitor with highly selective radiosensitizing activity, GSK635416A holds promise as a lead in the development of drugs active in potentiating radiotherapy for HNSCC and other cancer type