Repair of Oxidative DNA Damage and Cancer: Recent Progress in DNA Base Excision Repair

SIGNIFICANCE: Reactive oxygen species (ROS) are generated by exogenous and environmental genotoxins, but also arise from mitochondria as byproducts of respiration in the body. ROS generate DNA damage of which pathological consequence, including cancer is well established. Research efforts are intense to understand the mechanism of DNA base excision repair, the primary mechanism to protect cells from genotoxicity caused by ROS. RECENT ADVANCES: In addition to the notion that oxidative DNA damage causes transformation of cells, recent studies have revealed how the mitochondrial deficiencies and ROS generation alter cell growth during the cancer transformation. CRITICAL ISSUES: The emphasis of this review is to highlight the importance of the cellular response to oxidative DNA damage during carcinogenesis. Oxidative DNA damage, including 7,8-dihydro-8-oxoguanine, play an important role during the cellular transformation. It is also becoming apparent that the unusual activity and subcellular distribution of apurinic/apyrimidinic endonuclease 1, an essential DNA repair factor/redox sensor, affect cancer malignancy by increasing cellular resistance to oxidative stress and by positively influencing cell proliferation. FUTURE DIRECTIONS: Technological advancement in cancer cell biology and genetics has enabled us to monitor the detailed DNA repair activities in the microenvironment. Precise understanding of the intracellular activities of DNA repair proteins for oxidative DNA damage should provide help in understanding how mitochondria, ROS, DNA damage, and repair influence cancer transformation

Hirayama disease: a rare neurological condition of cervical cord pathology

The disease is characterized by a progressive muscle weakness and wasting of distal upper limb muscles sparing brachioradialis. The pathology is in the lower cervical cord due to forward displacement of dural sac and spinal cord by neck flexion. Repeated neck flexion may result in ischemia of the lower cervical anterior horns. The diagnosis can be confirmed by MRI, EMG. It requires a high degree of suspicion in a young patient presenting with unilateral upper limb distal muscle weakness with no sensory involvement, as early diagnosis will help in preventing the progression of the disease by employing simple measures like usage of a cervical collar. We report a case of a 25 year old man presenting with progressive distal upper limb muscle wasting, on investigating further diagnosed to have Hirayama disease

Polyubiquitination of Apurinic/Apyrimidinic Endonuclease 1 by Parkin

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein crucial for repair of oxidized DNA damage not only in genomic DNA but also in mitochondrial DNA. Parkin, a tumor suppressor and Parkinson\u27s disease (PD) associated gene, is an E3 ubiquitin ligase crucial for mitophagy. Although DNA damage is known to induce mitochondrial stress, Parkin\u27s role in regulating DNA repair proteins has not been elucidated. In this study, we examined the possibility of Parkin‐dependent ubiquitination of APE1. Ectopically expressed APE1 was degraded by Parkin and PINK1 via polyubiquitination in mouse embryonic fibroblast cells. PD‐causing mutations in Parkin and PINK1 abrogated APE1 ubiquitination. Interaction of APE1 with Parkin was observed by co‐immunoprecipitation, proximity ligation assay, and co‐localization in the cytoplasm. N‐terminal deletion of 41 amino acid residues in APE1 significantly reduced the Parkin‐dependent APE1 degradation. These results suggested that Parkin directly ubiquitinated N‐terminal Lys residues in APE1 in the cytoplasm. Modulation of Parkin and PINK1 activities under mitochondrial or oxidative stress caused moderate but statistically significant decrease of endogenous APE1 in human cell lines including SH‐SY5Y, HEK293, and A549 cells. Analyses of glioblastoma tissues showed an inverse relation between the expression levels of APE1 and Parkin. These results suggest that degradation of endogenous APE1 by Parkin occur when cells are stressed to activate Parkin, and imply a role of Parkin in maintaining the quality of APE1, and loss of Parkin may contribute to elevated APE1 levels in glioblastoma

Evaluation of pigeonpea genotypes for resistance to pigeonpea sterility Mmsaic Vvrus - B Isolate

Pigeonpea genotypes (89) were evaluated for resistance to Pigeonpea sterility mosaic virus Bangalore isolate (PPSMV-B). Of these, three genotypes, ICP 7035, MAL 14 and MAL 19, were found resistant, and two genotypes, ICP 6997 and ICP 8862, were tolerant to PPSMV-B. All the resistant lines tested negative to virus in enzyme-linked immunosorbent assay (ELISA) using PPSMV polyclonal antiserum. The resistant lines can be used in breeding programme for developing PPSMV-resistant high yielding cultivar

Evaluation of Advanced Peanut Breeding Lines for Resistance to Late Leaf Spot and Rust

Peanut (Arachis hypogaea L.) in India are grown in 6.7 million ha with a total production of 6.5 million t and an average productivity of <1 t/ha. The rainy season (June/July- Oct/Nov) is the main cropping season for peanut where the crop is grown generally under rainfed conditions. Rainy season productivity (0.8 t/ha) is much lower than that of the postrainy season. Late leaf spot (LLS) caused by Phaeoisariopsis personata..............

Genetic correlates of the development of theta event related oscillations in adolescents and young adults

The developmental trajectories of theta band (4–7 Hz) event-related oscillations (EROs), a key neurophysiological constituent of the P3 response, were assessed in 2170 adolescents and young adults ages 12 to 25. The theta EROs occurring in the P3 response, important indicators of neurocognitive function, were elicited during the evaluation of task-relevant target stimuli in visual and auditory oddball tasks. Associations between the theta EROs and genotypic variants of 4 KCNJ6 single nucleotide polymorphisms (SNPs) were found to vary with age, sex, scalp location, and task modality. Three of the four KCNJ6 SNPs studied here were found to be significantly associated with the same theta EROs in adults in a previous family genome wide association study. Since measures of the P3 response have been found to be a useful endophenotypes for the study of a number of clinical and behavioral disorders, studies of genetic effects on its development in adolescents and young adults may illuminate neurophysiological factors contributing to the onset of these conditions

ICP 7035 – A Sterility Mosaic Resistant Vegetable and Grain Purpose Pigeonpea Variety

ICP 7035 is a medium duration, non-determinate pigeonpea landrace collected in 1973 from Bedaghat (near Jabalpur), Madhya Pradesh, India. Plants mature in 170-200 days (in south-central regions of India) and, at this stage, reach an average height of 120-140 cm. Each plant produced around 100 pods and each pod contained 5 seeds, which are nutritionally rich and contain high percentages of digestible carbohydrates, vitamins and micronutrients. The large seeds (9-11 mm diameter) had purple seed coats and green cotyledons, and are suitable for consumption as vegetable. The fresh seed contains 8.6% protein, 12% fibre, and 45.7% carbohydrate and starch. The pinkish-purple colour of the pod and seed coat is due to high anthocyanin contents. While the normal sugar level in most pigeon pea cultivars is approximately 5%, the sugar content in ICP 7035 seeds is 8.8%. Decorticated dried split seeds measure 5-6 mm in diameter and 100 dried seeds weigh 19.2 g. The seed contains 19.6% protein, 27.4% dietary fibre, 33% starch and 67% carbohydrate, and has high amounts of copper, calcium, magnesium and phosphorous. Resistance to Pigeonpea sterility mosaic virus in ICP 7035 has a positive impact on yield as a result of negligible crop loss in endemic areas. In the absence of the disease, the yield of ICP 7035 is on a par with the yields of local cultivars. Recently, provisional approval was given for the release of this cultivar in SMD endemic areas of southern Karnataka

Predicting risk for Alcohol Use Disorder using longitudinal data with multimodal biomarkers and family history: a machine learning study.

Predictive models have succeeded in distinguishing between individuals with Alcohol use Disorder (AUD) and controls. However, predictive models identifying who is prone to develop AUD and the biomarkers indicating a predisposition to AUD are still unclear. Our sample (n = 656) included offspring and non-offspring of European American (EA) and African American (AA) ancestry from the Collaborative Study of the Genetics of Alcoholism (COGA) who were recruited as early as age 12 and were unaffected at first assessment and reassessed years later as AUD (DSM-5) (n = 328) or unaffected (n = 328). Machine learning analysis was performed for 220 EEG measures, 149 alcohol-related single nucleotide polymorphisms (SNPs) from a recent large Genome-wide Association Study (GWAS) of alcohol use/misuse and two family history (mother DSM-5 AUD and father DSM-5 AUD) features using supervised, Linear Support Vector Machine (SVM) classifier to test which features assessed before developing AUD predict those who go on to develop AUD. Age, gender, and ancestry stratified analyses were performed. Results indicate significant and higher accuracy rates for the AA compared with the EA prediction models and a higher model accuracy trend among females compared with males for both ancestries. Combined EEG and SNP features model outperformed models based on only EEG features or only SNP features for both EA and AA samples. This multidimensional superiority was confirmed in a follow-up analysis in the AA age groups (12-15, 16-19, 20-30) and EA age group (16-19). In both ancestry samples, the youngest age group achieved higher accuracy score than the two other older age groups. Maternal AUD increased the model's accuracy in both ancestries' samples. Several discriminative EEG measures and SNPs features were identified, including lower posterior gamma, higher slow wave connectivity (delta, theta, alpha), higher frontal gamma ratio, higher beta correlation in the parietal area, and 5 SNPs: rs4780836, rs2605140, rs11690265, rs692854, and rs13380649. Results highlight the significance of sampling uniformity followed by stratified (e.g., ancestry, gender, developmental period) analysis, and wider selection of features, to generate better prediction scores allowing a more accurate estimation of AUD development