DNA strand breaks, NAD metabolism, and programmed cell death

Da, Carson; Seto, Shiro; Db, Wasson; Carrera, CJ

doi:10.1016/0014-4827(86)90028-5

Cited by 286 publications

(93 citation statements)

References 48 publications

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“…36 We have previously shown that individuals differ in the number of DNA strand breaks formed after standard exposure of cells to bleomycin. 37 These differences may, however, be due both to different activities of DNA repair enzymes and/or to differences in factors such as cellular uptake or detoxification.…”

Section: Discussionmentioning

confidence: 99%

Reduced poly(ADP‐ribosyl)ation in lymphocytes of laryngeal cancer patients: Results of a case‐control study

Rajaee-Behbahani

Schmezer

Ramroth

et al. 2002

Intl Journal of Cancer

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Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme that is catalytically activated by DNA strand breaks, plays a complex role in DNA repair. Using NAD ؉ as a precursor, it catalyzes the formation of ADP-ribose polymers, which are attached to various proteins. Defects in DNA repair pathways have been associated with increased risks for cancer in humans. We investigated whether differences in the activity of PARP are associated with the risk for laryngeal cancer. In a case-control study on genetic, lifestyle and occupational risk factors for laryngeal cancer, PARP activity was assessed as DNA damage-induced poly(ADP-ribose) formation in human peripheral blood lymphocytes by quantitative immunofluorescence analysis. Polymer formation was determined as the cellular response to bleomycin, a well-known inducer of DNA strand breaks, in lymphocytes from 69 laryngeal cancer patients and 125 healthy controls. The frequency of bleomycin-induced polymer formation, measured as mean pixel intensity, was significantly lower in cases (74.6, SE ‫؍‬ 3.7) than in controls (94.5, SE ‫؍‬ 3.5) and not influenced by smoking, age or sex. There was no significant difference between cases (59.1, SE ‫؍‬ 5.2) and controls (50.5, SE ‫؍‬ 3.7) in basal polymer formation (in cells not treated with bleomycin). When the highest tertile of polymer formation was used as the reference, the odds ratio for the lowest tertile of bleomycininduced polymer formation was 3.79 (95% confidence interval 1.37-10.47, p ‫؍‬ 0.01). Peripheral blood lymphocytes from laryngeal cancer patients thus showed significantly less bleomycin-induced poly(ADP-ribose) formation. Our results suggest that a reduced capacity of somatic cells to synthesize poly(ADP-ribose) might be associated with an increased risk for laryngeal cancer. The underlying mechanism remains to be investigated. © 2002 Wiley-Liss, Inc. Key words: biomarker; bleomycin; molecular epidemiology; laryngeal cancer; poly(ADP-ribose) polymeraseLaryngeal carcinoma is the commonest tumor of the head and neck and the second commonest respiratory tract cancer after lung cancer in white persons. Respiratory cancers are paradigms of environmentally induced diseases and epidemiologic studies have identified smoking and alcohol intake as the most important risk factors. Other risk factors (poor nutrition, exposure to asbestos and other occupational exposures) have also been associated in some studies with the risk for laryngeal cancer. 1-3 These risk factors alone cannot, however, completely explain all cases of this cancer. Many studies have been conducted to identify biomarkers that reflect host susceptibility more closely. Those that have been found include variations in carcinogen metabolism, DNA adduct formation and DNA repair activity. 4,5 The pathogenic implications of these markers have been established for environmentally induced cancers such as lung tumors and head-and-neck squamous cell carcinoma. 6,7 An important reaction in DNA repair pathways is poly(ADP-ribosyl)ation, which is induced by the presence ...

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Section: Discussionmentioning

confidence: 99%

Reduced poly(ADP‐ribosyl)ation in lymphocytes of laryngeal cancer patients: Results of a case‐control study

Rajaee-Behbahani

Schmezer

Ramroth

et al. 2002

Intl Journal of Cancer

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“…One problem in relying on measurements of lipid peroxidation as an index of free radical reac- [21,30], and/or to impairments in the regulation of intracellular Ca2+ concentration, may be the primary toxic mechanisms.…”

Section: Introductionmentioning

confidence: 99%

The measurement of free radical reactions in humans

Halliwell¹,

Grootveld²

1987

FEBS Letters

304

143

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“…PARP-1 uses ␤-nicotinamide adenine dinucleotide (NAD ϩ ) as its substrate. Because PARP-1 is an abundant enzyme (2% of nuclear protein) and has a high turnover number, its activation can deplete cellular NAD ϩ levels (8)(9)(10). Cellular perturbations that lead to necrosis cause such ''overactivation,'' leading to NAD ϩ depletion.…”

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confidence: 99%

Poly(ADP-ribose) polymerase-1 is required for efficient HIV-1 integration

Juluri

Zhou

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) is an abundant nuclear enzyme, activated by DNA strand breaks to attach up to 200 ADP-ribose groups to nuclear proteins. As retroviral infection requires integrase-catalyzed DNA strand breaks, we examined infection of pseudotyped HIV type I in fibroblasts from mice with a targeted deletion of PARP-1. Viral infection is almost totally abolished in PARP-1 knockout fibroblasts. This protection from infection reflects prevention of viral integration into the host genome. These findings suggest a potential for PARP inhibitors in therapy of HIV type I infection.

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DNA strand breaks, NAD metabolism, and programmed cell death

Cited by 286 publications

References 48 publications

Reduced poly(ADP‐ribosyl)ation in lymphocytes of laryngeal cancer patients: Results of a case‐control study

Reduced poly(ADP‐ribosyl)ation in lymphocytes of laryngeal cancer patients: Results of a case‐control study

The measurement of free radical reactions in humans

Poly(ADP-ribose) polymerase-1 is required for efficient HIV-1 integration

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