Biomedical subjects

Sascha Beneke

Publications and source records attributed to Sascha Beneke.

7 recordsLinked to original sources

PubMed2005

Ageing and PARP.

Poly(ADP-ribosyl)ation, which is the posttranslational modification of proteins with poly(ADP-ribose), is catalysed by poly(ADP-ribose) polymerases. DNA-strand break induced catalytic activation of two PARP isoforms, namely PARP-1 and -2, are in involved in DNA base-excision repair and other repair pathways. A body of correlative data suggests a link between DNA-damage induced poly(ADP-ribosyl)ation and mammalian longevity. This notion was reinforced by recently published evidence for interactions between PARP-1 and the Werner syndrome protein, deficiency of which causes premature ageing in humans. Recent research on PARPs and poly(ADP-ribose) provides several candidate mechanisms through which poly(ADP-ribosyl)ation might contribute to keeping the ageing process at slow pace.

Aging↗

PubMed2004

The emerging role of poly(ADP-ribose) polymerase-1 in longevity.

In the present paper, the involvement of the family of poly(ADP-ribose) polymerases (PARPs), and especially of PARP-1, in mammalian longevity is reviewed. PARPs catalyse poly(ADP-ribosyl)ation, a covalent post-translational protein modification in eukaryotic cells. PARP-1 and PARP-2 are activated by DNA strand breaks, play a role in DNA base-excision repair (BER) and are survival factors for cells exposed to low doses of ionising radiation or alkylating agents. PARP-1 is the main catalyst of poly(ADP-ribosyl)ation in living cells under conditions of DNA breakage, accounting for about 90% of cellular poly(ADP-ribose). DNA-damage-induced poly(ADP-ribosyl)ation also functions as a negative regulator of DNA damage-induced genomic instability. Cellular poly(ADP-ribosyl)ation capacity in permeabilised mononuclear blood cells (MNC) is positively correlated with life span of mammalian species. Furthermore PARP-1 physically interacts with WRN, the protein deficient in Werner syndrome, a human progeroid disorder, and PARP-1 and WRN functionally cooperate in preventing carcinogenesis in vivo. Some of the other members of the PARP family have also been revealed as important regulators of cellular functions relating to ageing/longevity. In particular, tankyrase-1, tankyrase-2, PARP-2 as well as PARP-1 have been found in association with telomeric DNA and are able to poly(ADP-ribosyl)ate the telomere-binding proteins TRF-1 and TRF-2, thus blocking their DNA-binding activity and controlling telomere extension by telomerase.

Animals↗

PubMed2004

Poly(ADP-ribosyl)ation, PARP, and aging.

Poly(ADP-ribose) polymerases (PARPs) catalyze the poly(ADP-ribosyl)ation of proteins. This posttranslational modification, as generated by the DNA damage-activated enzymes PARP-1 and -2, has long been known to be involved in DNA repair. Correlative data have suggested an association between DNA damage-induced poly(ADP-ribosyl)ation and mammalian longevity, and this link has recently been strengthened by the discovery of interactions between PARP-1 and the Werner syndrome protein. Emerging additional members of the PARP family display different cellular localizations and are involved in diverse processes such as the regulation of telomere or centrosome function, thereby providing further, independent links between poly(ADP-ribosyl)ation and the aging process.

Aging↗

PubMed2004

Poly(ADP-ribosyl)ation inhibitors: promising drug candidates for a wide variety of pathophysiologic conditions.

Poly(ADP-ribose) polymerases are involved in many aspects of regulation of cellular functions. Using NAD+ as a substrate, they catalyse the covalent transfer of ADP-ribose units onto several acceptor proteins to form a branched ADP-ribose polymer. The best characterised and first discovered member of this multiprotein family is PARP-1. Its catalytic activity is markedly stimulated upon binding to DNA strand interruptions, and the resulting polymer is thought to function in chromatin relaxation as well as in signalling the presence of damage to DNA repair complexes and in regulating enzyme activities. Moderate activation of PARP-1 facilitates the efficient repair of DNA damage arising from monofunctional alkylating agents, reactive oxygen species or ionising radiation, but severe genotoxic stress leads to rapid energy consumption and subsequently to necrotic cell death. The latter aspect of PARP-1 activity has been implicated in the pathogenesis of various clinical conditions such as shock, ischaemia-reperfusion and diabetes. Inhibition of ADP-ribose polymer formation has been shown to be effective, on the one hand, in the treatment of cancer in combination with alkylating agents by suppressing DNA repair and thus driving tumour cells into apoptosis, and on the other hand it appears to be a promising drug target for the treatment of pathologic conditions involving oxidative stress. In view of the existence of several members of the PARP family in mammalian cells, one has to be aware of possible side effects but also of a wide spectrum of potential clinical applications, which calls for the development of more specific inhibitors.

Acute Disease↗

PubMed2003

L-selegiline potentiates the cellular poly(ADP-ribosyl)ation response to ionizing radiation.

DNA strand breaks induced by alkylating agents, oxidants, or ionizing radiation trigger the covalent modification of nuclear proteins with poly(ADP-ribose), which is catalyzed for the most part by poly(ADP-ribose) polymerase-1 and plays a role in DNA base-excision repair. Poly(ADP-ribosyl)ation capacity of mononuclear blood cells correlates positively with life span of mammalian species. Here, we show that l-selegiline, an anti-Parkinson drug with neuroprotective activity and life span-extending effect in laboratory animals, can potentiate gamma-radiation-induced poly(ADP-ribose) formation in intact cells. COR4 hamster cells were incubated with l-selegiline (50 nM) for various time periods, followed by gamma-irradiation (45 Gy). Quantification of cellular poly(ADP-ribose) levels at 10 min after starting the irradiation revealed significant increases (up to 1.8-fold) in cells preincubated with the drug for 8 h to 7 days compared with drug-free irradiated controls. There was no selegiline-induced change in poly(ADP-ribose) levels of unirradiated cells nor in basal or radiation-induced DNA strand breaks, respectively. Surprisingly, poly(ADP-ribose) polymerase-1 protein was down-regulated by l-selegiline treatment. Addition of l-selegiline to purified poly(ADP-ribose) polymerase-1 did not alter enzymatic activity. In conclusion, the results of the present study identify a novel intervention to potentiate the cellular poly(ADP-ribosyl)ation response. We hypothesize that the effect of l-selegiline is due to modulation of accessory proteins regulating poly(ADP-ribose) polymerase-1 activity and that increased cellular poly- (ADP-ribosyl)ation capacity may contribute to the neuroprotective potential and/or life span extension afforded by l-selegiline.

Animals↗

PubMedDate not supplied

Poly(ADP-ribosyl)ation and aging.

Poly(ADP-ribosyl)ation is a DNA strand break-driven post-translational modification of proteins catalyzed by poly(ADP-ribose) polymerase-1 (PARP-1), with NAD+ serving as substrate. Poly(ADP-ribosyl)ation is triggered by DNA strand breaks, is functionally associated with DNA repair pathways and is a survival factor for cells under low to moderate levels of genotoxic stress. We have previously described a positive correlation between poly(ADP-ribosyl)ation capacity of mononuclear blood cells with longevity of mammalian species. Our comparison of purified recombinant human and rat PARP-1 revealed that this correlation might be explained in part by evolutionary sequence divergence. We have also developed molecular genetic approaches to modulate the poly(ADP-ribosyl)ation status in living cells. Our results revealed that PARP-1 acts as a negative regulator of DNA damage-induced genomic instability, the latter being known as an important driving force for carcinogenesis. Our recent data obtained in transgenic mice with selective expression of a dominant negative version of PARP-1 in basal skin keratinocytes indicate that PARP-1 activity suppresses skin papilloma formation in a two-stage skin carcinogenesis protocol. It is tempting to speculate that increased poly(ADP-ribosyl)ation capacity in long-lived species might help retard the accumulation of DNA damage and of mutations and thus slow down the rate of aging and of carcinogenesis more efficiently as compared with short-lived animals.

Aged↗

PubMedDate not supplied

Poly(ADP-ribose) polymerase-1, DNA repair and mammalian longevity.

Cellular DNA repair activities can be expected to control the rate of the ageing process by keeping the steady-state levels of DNA damage, which is continuously induced by endogenous and exogenous damaging agents, at low levels. Poly(ADP-ribosyl)ation is one of the immediate biochemical reactions of eukaryotic cells to DNA damage and is functionally associated with DNA base-excision repair and strand break repair. Here we review the current state of the art concerning the relationship between DNA strand break repair, poly(ADP-ribosyl)ation, maintenance of genomic stability and mammalian life span.

Aging↗