A role for protein phosphatase 4 in regulating non-homologous end-joining

Comment on: Liu J, et al. Cell Cycle 2012; 11:2643-9.     

DNA repair mechanisms in dividing and non-dividing cells

DNA damage created by endogenous or exogenous genotoxic agents can exist in multiple forms, and if allowed to persist, can promote genome instability and directly lead to various human diseases, particularly cancer, neurological abnormalities, immunodeficiency and premature aging. To avoid such deleterious outcomes, cells have evolved an array of DNA repair pathways, which carry out what is typically a multiple-step process to resolve specific DNA lesions and maintain genome integrity. To fully appreciate the biological contributions of the different DNA repair systems, one must keep in mind the cellular context within which they operate. For example, the human body is composed of non-dividing and dividing cell types, including, in the brain, neurons and glial cells. We describe herein the molecular mechanisms of the different DNA repair pathways, and review their roles in non-dividing and dividing cells, with an eye toward how these pathways may regulate the development of neurological disease.     

Characterization of the first adult de novo case of 46,X,der(Y)t(X;Y)(p22.3;q11.2)

Herein, we describe a case of an infertile man detected in postnatal diagnosis with FISH characterization and array-CGH used for genome-wide screening which allowed the identification of a complex rearrangement involving sex chromosomes, apparently without severe phenotypic consequences. The deletion detected in our patient has been compared with previously reported cases leading us to propose a hypothetical diagnostic algorithm that would be useful in similar clinical situations, with imperative multi disciplinary approach integrated with genetic counseling. Our patient, uniquely of reproductive age, is one of six reported cases of duplication of Xp22.3 (~ 8.4 Mb) segment and contemporary deletion of Yq (~ 42.9 Mb) with final karyotype as follows:

46,X,der(Y),t(X;Y)(Ypter → Yq11.221::Xp22.33 → Xpter).ish der(Y) (Yptel+,Ycen+,RP11-529I21+,RP11-506M9-Yqtel −,Xptel +). arrXp22.33p22.31(702–8,395,963, 8,408,289x1), Yq11.221q12 (14,569,317x1, 14,587,321–57,440,839x0)     

DNA-damage response in chromatin of ribosomal genes and the surrounding genome

DNA repair events have functional significance especially for genome stability. Although the DNA damage response within the whole genome has been extensively studied, the region-specific characteristics of nuclear sub-compartments such as the nucleolus or fragile sites have not been fully elucidated. Here, we show that the heterochromatin protein HP1 and PML protein recognize spontaneously occurring 53BP1- or γ-H2AX-positive DNA lesions throughout the genome. Moreover, 53BP1 nuclear bodies, which co-localize with PML bodies, also occur within the nucleoli compartments. Irradiation of the human osteosarcoma cell line U2OS with γ-rays increases the degree of co-localization between 53BP1 and PML bodies throughout the genome; however, the 53BP1 protein is less abundant in chromatin of ribosomal genes and fragile sites (FRA3B and FRA16D) in γ-irradiated cells. Most epigenomic marks on ribosomal genes and fragile sites are relatively stable in both non-irradiated and γ-irradiated cells. However, H3K4me2, H3K9me3, H3K27me3 and H3K79me1 were significantly changed in promoter and coding regions of ribosomal genes after exposure of cells to γ-rays. In fragile sites, γ-irradiation induces a decrease in H3K4me3, changes the levels of HP1β, and modifies the levels of H3K9 acetylation, while the level of H3K9me3 was relatively stable. In these studies, we confirm a specific DNA-damage response that differs between the ribosomal genes and fragile sites, which indicates the region-specificity of DNA repair.     

Effects of combined centrifugation and ultraviolet irradiation of eggs on pattern formation in Chironomus embryos

Summary

Combined mild centrifugation and uv irradiation of Chironomus embryos modified the developmental types expected from centrifugation alone, somewhat differently from the combined strong centrifugation and uv irradiation of Smittia embryos. The modifications changed with the stages irradiated. The change caused by anterior irradiation may depend on whether or not a part of the cytoplasmic zone is irradiated simultaneously with the anterior yolky end; because most of the cytoplasm lies in the posterior half of egg at early irradiation, while the tip of the cytoplasm redistributes near the anterior end by the late irradiation. Early uv irradiation of the anterior end of centrifuged eggs, causing the formation of a double abdomen (DA) or an inverted embryo, is not photoreversible, while the uv damage to the anterior end of uncentrifuged eggs, inducing DA, is. These facts suggest that there is another photoirreversible uv target in addition to the photoreversible target for DA induction or the anterior determinant shown in Smittia. Other changes, such as the induction of a double cephalon by late irradiation of the centrifuged egg, are photoreversible, but in an unusual way in that the level of photorecovery is similar to the result of incubation in the dark after early irradiation, and not to that of the centrifuged controls. These modified results were then compared with those for Smittia embryos.     

Alleviation of chromium toxicity in rice seedlings by applying exogenous glutathione

The effect of exogenous reduced glutathione (GSH) on alleviation of hexavalent chromium (Cr⁶⁺) toxicity to rice seedlings and its physiological mechanisms were comprehensively investigated in a series of experiments. Our results showed that growth and nutrient uptake of rice seedlings were dramatically reduced under 100 μM Cr⁶⁺ stress, and the reduction was significantly alleviated by exogenous GSH. Cr⁶⁺ stress also reduced cell viability in root tips and damaged ultrastructure of both chloroplasts and root cells, while the addition of GSH alleviates those negative effects. Cr-induced toxicity and GSH-caused Cr alleviation differed significantly between Cr-tolerant Line 117 (L117) and Cr-sensitive Line 41 (L41). Under Cr⁶⁺ stress, cystine content was increased and GSH content was decreased in rice plants, exogenous GSH, however, mitigated the Cr-toxicity by reversing the Cr-induced changes of the two compounds. The types of Cr-induced secretion of organic acids varied between the genotypes, where reduction in the contents of acetic and lactic acids and tartaric and malic acids were observed in L117 and L41, respectively. The addition of GSH alleviated the reduction of secretion of these organic acids. Exogenous GSH also altered the forms of Cr ions in the rhizosphere and the fraction of distribution at subcellular level in both shoots and roots. It may be concluded that the alleviation of Cr⁶⁺ toxicity by exogenous GSH is directly attributed to its regulation on forms of Cr ions in rhizosphere and their distribution at subcellular levels.