Poly(ADP-ribose) polymerase enzymes and the maintenance of genome integrity.

DNA damage response (DDR) relies on swift and accurate signaling to rapidly identify DNA lesions and initiate repair. A critical DDR signaling and regulatory molecule is the posttranslational modification poly(ADP-ribose) (PAR). PAR is synthesized by a family of structurally and functionally diverse proteins called poly(ADP-ribose) polymerases (PARPs). Although PARPs share a conserved catalytic domain, unique regulatory domains of individual family members endow PARPs with unique properties and cellular functions. Family members PARP-1, PARP-2, and PARP-3 (DDR-PARPs) are catalytically activated in the presence of damaged DNA and act as damage sensors. Family members tankyrase-1 and closely related tankyrase-2 possess SAM and ankyrin repeat domains that regulate their diverse cellular functions. Recent studies have shown that the tankyrases share some overlapping functions with the DDR-PARPs, and even perform novel functions that help preserve genomic integrity. In this review, we briefly touch on DDR-PARP functions, and focus on the emerging roles of tankyrases in genome maintenance. Preservation of genomic integrity thus appears to be a common function of several PARP family members, depicting PAR as a multifaceted guardian of the genome.

Anti-oxidative or anti-inflammatory additives reduce ischemia/reperfusions injury in an animal model of cardiopulmonary bypass.

Severe inborn cardiac malformations are typically corrected in cardioplegia, with a cardio-pulmonary bypass (CPB) taking over body circulation. During the operation the arrested hearts are subjected to a global ischemia/reperfusion injury. Although the applied cardioplegic solutions have a certain protective effect, application of additional substances to reduce cardiac damage are of interest.18 domestic piglets (10-15 kg) were subjected to a 90 min CPB and a 120 min reperfusion phase without or with the application of epigallocatechin-3-gallate (10 mg/kg body weight) or minocycline (4 mg/kg body weight), with both drugs given before and after CPB. 18 additional sham-operated piglets without or with epigallocatechin-3-gallate or minocycline served as controls. In total 36 piglets were analyzed (3 CPB-groups and 3 control groups without or with epigallocatechin-3-gallate or minocycline respectively; 6 piglets per group). Hemodynamic and blood parameters and ATP-measurements were assessed. Moreover, a histological evaluation of the heart muscle was performed. RESULTS: Piglets of the CPB-group needed more catecholamine support to achieve sufficient blood pressure. Ejection fraction and cardiac output were not different between the 6 groups. However, cardiac ATP-levels and blood lactate were significantly lower and creatine kinase was significantly higher in the three CPB-groups. Markers of apoptosis, hypoxia, nitrosative and oxidative stress were significantly elevated in hearts of the CPB-group. Nevertheless, addition of epigallocatechin-3-gallate or minocycline significantly reduced markers of myocardial damage. Noteworthy, EGCG was more effective in reducing markers of hypoxia, whereas minocycline more efficiently decreased inflammation. CONCLUSIONS: While epigallocatechin-3-gallate or minocycline did not improve cardiac hemodynamics, markers of myocardial damage were significantly lower in the CPB-groups with epigallocatechin-3-gallate or minocycline supplementation.

Quantification of DNA Damage in Heart Tissue as a Novel Prediction Tool for Therapeutic Prognosis of Patients With Dilated Cardiomyopathy.

This study evaluated myocardial nuclear staining for the DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in 58 patients with dilated cardiomyopathy. Patients with left ventricular reverse remodeling (LVRR) showed a significantly smaller proportion of PAR-positive nuclei and γ-H2A.X-positive nuclei in biopsy specimens compared with those without LVRR. Propensity analysis showed that the proportion of both PAR-positive and γ-H2A.X-positive nuclei were independent prognostic factors for LVRR. In conclusion, we showed the utility of DNA damage-marker staining to predict the probability of LVRR, thus revealing a novel prognostic predictor of medical therapy for dilated cardiomyopathy.

Nitrosative Stress as a Modulator of Inflammatory Change in a Model of Takotsubo Syndrome.

Previous studies have shown that patients with Takotsubo syndrome (TS) have supranormal nitric oxide signaling, and post-mortem studies of TS heart samples revealed nitrosative stress. Therefore, we first showed in a female rat model that isoproterenol induces TS-like echocardiographic changes, evidence of nitrosative stress, and consequent activation of the energy-depleting enzyme poly(ADP-ribose) polymerase-1. We subsequently showed that pre-treatment with an inhibitor of poly(ADP-ribose) polymerase-1 ameliorated contractile abnormalities. These findings thus add to previous reports of aberrant ß-adrenoceptor signaling (coupled with nitric oxide synthase activation) to elucidate mechanisms of impaired cardiac function in TS and point to potential methods of treatment.

ISWI chromatin remodeling complexes in the DNA damage response.

Regulation of chromatin structure is an essential component of the DNA damage response (DDR), which effectively preserves the integrity of DNA by a network of multiple DNA repair and associated signaling pathways. Within the DDR, chromatin is modified and remodeled to facilitate efficient DNA access, to control the activity of repair proteins and to mediate signaling. The mammalian ISWI family has recently emerged as one of the major ATP-dependent chromatin remodeling complex families that function in the DDR, as it is implicated in at least 3 major DNA repair pathways: homologous recombination, non-homologous end-joining and nucleotide excision repair. In this review, we discuss the various manners through which different ISWI complexes regulate DNA repair and how they are targeted to chromatin containing damaged DNA.