PARP-2 depletion results in lower radiation cell survival but cell line-specific differences in poly(ADP-ribose) levels.

Poly(ADP-ribose) polymerase-2 (PARP-2) activity contributes to a cells' poly(ADP-ribosyl)ating potential and like PARP-1, has been implicated in several DNA repair pathways including base excision repair and DNA single strand break repair. Here the consequences of its stable depletion in HeLa, U20S, and AS3WT2 cells were examined. All three PARP-2 depleted models showed increased sensitivity to the cell killing effects on ionizing radiation as reported in PARP-2 depleted mouse embryonic fibroblasts providing further evidence for a role in DNA strand break repair.

Variations in the mRNA expression of poly(ADP-ribose) polymerases, poly(ADP-ribose) glycohydrolase and ADP-ribosylhydrolase 3 in breast tumors and impact on clinical outcome.

In order to assess the variation in expression of poly(ADP-ribose) polymerase (PARP) family members and the hydrolases that degrade the poly(ADP-ribose) polymers they generate and possible associations with classical pathological parameters, including long-term outcome, the mRNA levels of PARP1, PARP2, PARP3, poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3) were examined using quantitative reverse transcription polymerase chain reaction in 443 unilateral invasive breast cancers and linked to hormonal status, tumor proliferation and clinical outcome. PARP1 mRNA levels were the highest among these five genes in both normal and tumor tissues, with a 2.45-fold higher median level in tumors compared to normal tissues.

The impact of cyclin-dependent kinase 5 depletion on poly(ADP-ribose) polymerase activity and responses to radiation.

Cyclin-dependent kinase 5 (Cdk5) has been identified as a determinant of sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Here, the consequences of its depletion on cell survival, PARP activity, the recruitment of base excision repair (BER) proteins to DNA damage sites, and overall DNA single-strand break (SSB) repair were investigated using isogenic HeLa stably depleted (KD) and Control cell lines. Synthetic lethality achieved by disrupting PARP activity in Cdk5-deficient cells was confirmed, and the Cdk5(KD) cells were also found to be sensitive to the killing effects of ionizing radiation (IR) but not methyl methanesulfonate or neocarzinostatin.

Poly(ADP-ribose) polymerase-1 (PARP-1) pharmacogenetics, activity and expression analysis in cancer patients and healthy volunteers.

There is a wide inter-individual variation in PARP-1 {PAR [poly(ADP-ribose)] polymerase 1} activity, which may have implications for health. We investigated if the variation: (i) is due to polymorphisms in the PARP-1 gene or PARP-1 protein expression; and (ii) affects patients' response to anticancer treatment. We studied 56 HV (healthy volunteers) and 118 CP (cancer patients) with supporting in vivo experiments.

[Oxidative DNA damage--analysis and clinical significance].

Oxidative damage DNA is aninevitable, natural consequence of cellular metabolism resulting from formation of reactive oxygen species (ROS) including free oxygen radicals. However, the level ofthe damage may increase under conditions of oxidative stress, arising from exposure to a variety of physical or chemical insults. In this review we present the mechanisms by which oxidative damage to DNA may lead to pathological processes involved in the development of cancer, cardiovascular diseases and ageing.

Uracil in DNA--its biological significance.

Uracil may arise in DNA as a result of spontaneous cytosine deamination and/or misincorporation of dUMP during DNA replication. In this paper we will review: (i) sources of the origin of uracil in DNA; (ii) some properties of the enzymes responsible for the excision of uracil and their role in the Ig diversification process, which comprises somatic hypermutation and class switch recombination; and (iii) consequences of cytosine deamination in other than the Ig loci, in cell types different than B lymphocytes. Furthermore, the issue concerning the basal level of uracil in DNA and consequences of the presence of U:A pairs for DNA stability and cell functions will be discussed.

Doxorubicin-induced suppression of poly(ADP-ribose) polymerase-1 (PARP-1) activity and expression and its implication for PARP inhibitors in clinical trials.

Purpose: Monozygotic twins provide an excellent tool to study environmental effects on human health. Poly(ADP-ribose) polymerase-1 (PARP-1) is an important enzyme primarily involved in DNA repair and genomic stability and is under clinical investigation as a target for anticancer therapy. As a part of a PARP pharmacogenetics study, elderly male monozygotic twins, one healthy and the other with a Trojani grade 3 sarcoma treated with doxorubicin (DOX: 142.

PARP inhibitor development for systemic cancer targeting.

Poly(ADP-ribose) polymerase 1 (PARP-1) is a DNA-binding enzyme that is activated by DNA breaks, converting them into an intracellular signal via poly(ADP-ribosyl)ation of nuclear proteins. Negatively charged polymers of ADP-ribose (PAR) attached to PARP-1 itself and histones lead to chromatin relaxation, facilitating the access of base excision/single strand break repair proteins and activating these repair enzymes. PARP inhibitors have been developed to investigate the role of PARP-1 in cell biology and to overcome DNA repair-mediated resistance of cancer cells to cytotoxic therapy.