The adduct formation between the thioguanine-polyamine ligands and DNA with the AP site under UVA irradiated and non-irradiated conditions

The AP sites are representative of DNA damage and known as an intermediate in the base excision repair (BER) pathway which is involved in the repair of damaged nucleobases by reactive oxygen species, UVA irradiation, and DNA alkylating agents. Therefore, it is expected that the inhibition or modulation of the AP site repair pathway may be a new type of anticancer drug. In this study, we investigated the effects of the thioguanine-polyamine ligands (^SG-ligands) on the affinity and the reactivity for the AP site under UVA irradiated and non-irradiated conditions. The ^SG-ligands have a photo-reactivity with the A-F-C sequence where F represents a tetrahydrofuran AP site analogue. Interestingly, the ^SG-ligands promoted the β-elimination of the AP site followed by the formation of a covalent bond with the β-eliminated fragment without UVA irradiation.     

Inner structural organization of the mandibular corpus in the late Early Pleistocene human specimens Tighenif 1 and Tighenif 2

The present study investigates the inner structural organization of the two mandible specimens Tighenif 1 and Tighenif 2 from the late early Pleistocene site of Tighenif, Algeria. Using (micro)tomographic scans, we built a new protocol to investigate the cortical bone topography at the post-canine level. We selected two cross-sectional slices placed between the P3/P4 and M1/M2 on the right and left sides and assessed the cortical bone thickness topography (CBT) on each slice. Our analyses demonstrate that the mandibles from Tighenif exhibit higher CBT and a different topographic distribution pattern at the molar level than in modern humans, resulting in a proportionally more robust inner structure, while a similar signal is observed between the fossil and extant specimens at the premolar level. Further studies need to be done in order to determine if this feature is related to functional constraints during mastication or paramasticatory activities; or if it is related to any independent evolutionary process.     

Wnt and BMP signaling pathways co-operatively induce the differentiation of multiple myeloma mesenchymal stem cells into osteoblasts by upregulating EMX2

Osteoblast differentiation, defined as the process whereby a relatively unspecialized cell acquires the specialized features of an osteoblast, is directly linked to multiple myeloma (MM) bone disease. Wnt and bone morphogenetic protein (BMP) are proved to be implicated in the pathological or defective osteoblast differentiation process. This study aims to test the involvement of Wnt, bone morphogenetic proteins (BMP) pathways, and empty spiracles homeobox 2 (EMX2) in osteoblast differentiation and MM development. Initially, differentially expressed genes in bone marrow mesenchymal stem cells (MSCs) from MM patients and healthy donors were identified using microarray-based gene expression profiling. The functional role of Wnt and BMP in MM was determined. Next, we focused on the co-operative effects of Wnt and BMP on calcium deposition, alkaline phosphatase (ALP) activity, the number of mineralized nodules, and osteocalcin (OCN) content in MSCs. The expression patterns of Wnt and BMP pathway–related genes, EMX2 and osteoblast differentiation-related factors were determined to assess their effects on osteoblast differentiation. Furthermore, regulation of Wnt and BMP in ectopic osteogenesis was also investigated in vivo. An integrated genomic screen suggested that Wnt and BMP regularly co-operate to regulate EMX2 and affect MM. EMX2 was downregulated in MSCs. The activated Wnt and BMP resulted in more calcium salt deposits, mineralized nodules, and a noted increased in ALP activity and OCN content by upregulating EMX2, leading to induced differentiation of MSCs into osteoblasts. Collectively, this study demonstrated that Wnt and BMP pathways could co-operatively stimulate differentiation of MSCs into osteoblasts and inhibit MM progression, representing potential targets for MM treatment.     

BLM has Contrary Effects on Repeat-Mediated Deletions,based on the Distance of DNA DSBs to a Repeat and Repeat Divergence

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Automethylation of protein (d -aspartyl/l -isoaspartyl) carboxyl methyltransferase, a response to enzyme aging

A question that is central to understanding the mechanisms of aging and cellular deterioration is whether enzymes involved in recognition and metabolism of spontaneously damaged proteins are themselves damaged, either becoming substrates for their own activity; or being unable to act upon themselves, initiating cascades of cellular damage. We show here byin vitro experiments that protein (d-aspartyl/l-isoaspartyl) carboxyl methyltransferase (PCM) from bovine erythrocytes does methylate age-dependent amino acid damage in its own sequence. The subpopulation that is methylated, termed thePCM fraction, appears to be formed through age-dependent deamidation of an asparaginyl site to either anl-isoaspartyl ord-aspartyl site because (a) the stoichiometry of automethylation of purified PCM is less than 1%, a value typical of the substoichiometric methylation of many other aged protein substrates, (b)PCM is slightly more acidic than the bulk of PCM, and (c) the methyl esterified site inPCM has the characteristic base-lability of this type of methyl ester. Also, the methyl group is not incorporated into the enzyme as an active site intermediate because the incorporated methyl group is not chased onto substrate protein. The effect of enzyme dilution on the rate of the automethylation reaction is consistent with methylation occurring between protein molecules, showing that the pool of PCM is autocatalytic even though individual molecules may not be. The automethylation and possible self-repair of the PCM pool has implications for maintaining thein vivo efficiency of methylation-dependent protein repair.     

Damage and mutagenesis of E. coli and bacteriophage λ induced by oxathiolane and aziridinyl steroids

λ-Escherichia coli complexes exhibited remarkable sensitivity to the treatment with test steroidal derivatives in the presence of Cu(II). The decline in plaque-forming units after steroid treatment was more pronounced in complexes with some of the irradiation repair-defective mutants of E. coli K-12, i.e., recA, lexA and polA, as compared to uvrA and wild-type strains. The red gene of λ phage and recA gene of E. coli seem to have a complementary effect on the steroid-induced lesions. An enhanced level of mutagenesis was observed when steroid-treated E. coli cells were transformed with steroid-treated pBR322 plasmid DNA. A remarkable degree of c mutation was also observed when steroid I-treated phage particles were allowed to adsorb on steroid-treated wild-type bacteria. Moreover, the oxathione steroid treatment of λcI857-E. coli lysogen resulted in prophage induction in nutrient broth even at 32°C. Thus on the basis of these results, the role of SOS repair system in steroid-induced mutagenesis and repair of DNA lesions in E. coli and bacteriophage λ has been suggested.     

Protein interactions between surface annexin A2 and S100A10 mediate adhesion of breast cancer cells to microvascular endothelial cells

Annexin A2 (AnxA2) and S100A10 are known to form a molecular complex. Using fluorescence-based binding assays, we show that both proteins are localised on the cell surface, in a molecular form that allows mutual interaction. We hypothesized that binding between these proteins could facilitate cell–cell interactions. For cells that express surface S100A10 and surface annexin A2, cell–cell interactions can be blocked by competing with the interaction between these proteins. Thus an annexin A2-S100A10 molecular bridge participates in cell–cell interactions, revealing a hitherto unexplored function of this protein interaction.     

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.