Transposable elements and human cancer: A causal relationship?

Transposable elements are present in almost all genomes including that of humans. These mobile DNA sequences are capable of invading genomes and their impact on genome evolution is substantial as they contribute to the genetic diversity of organisms. The mobility of transposable elements can cause deleterious mutations, gene disruption and chromosome rearrangements that may lead to several pathologies including cancer. This mini-review aims to give a brief overview of the relationship that transposons and retrotransposons may have in the genetic cause of human cancer onset, or conversely creating protection against cancer. Finally, the cause of TE mobility may also be the cancer cell environment itself.     

Association between the XRCC3 T241M polymorphism and risk of cancer: Evidence from 157 case–control studies

The T241M polymorphism in the X-ray cross-complementing group 3 (XRCC3) had been implicated in cancer susceptibility. The previous published data on the association between XRCC3 T241M polymorphism and cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and XRCC3 T241M (61,861 cases and 84,584 controls from 157 studies) polymorphism in different inheritance models. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ration [OR] = 1.07, 95% confidence interval [CI] = 1.00–1.13; recessive model: OR = 1.15, 95% CI = 1.08–1.23; additive model: OR = 1.17, 95% CI = 1.08–1.28) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk remained for subgroups of bladder cancer and breast cancer, especially in Caucasians. In addition, significantly decreased lung cancer risk was also observed. In summary, this meta-analysis suggests the participation of XRCC3 T241M in the susceptibility for bladder cancer and breast cancer, especially in Caucasians, and XRCC3 T241M polymorphism is associated with decreased lung cancer risk. Moreover, our work also points out the importance of new studies for T241M association in some cancer types, such as gastric cancer, colorectal cancer, and melanoma skin cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the XRCC3 polymorphism in cancer development.     

S-Carboxymethylcysteine Synthase from Escherichia coli

An enzyme that catalyzes the synthesis of S-carboxymethyl- l-cysteine from 3-chloro- l-alanine (3-Cl-Ala) and thioglycolic acid was found in Escherichia coli W3110 and was designated as S- carboxymethyl-l-cysteine synthase. It was purified from the cell-free extract to electrophoretic homogeneity and was crystallized. The enzyme has a molecular weight of 84,000 and gave one band corresponding to a molecular weight of 37,000 on SDS-polyacrylamide gel electrophoresis. The purified enzyme catalyzed the β-replacement reactions between 3-CI-AIa and various thiol compounds. The apparent Km values for 3-Cl-Ala and thioglycolic acid were 40 mM and 15.4 mM. The enzyme showed very low activity as to the α,β-elimination reaction with 3-Cl-Ala and l-serine. It was not inactivated on the incubation with 3-Cl-Ala. The absorption spectrum of the enzyme shows a maximum at 412 nm, indicating that it contains pyridoxal phosphate as a cofactor. The N-terminal amino acid sequence was determined and the corresponding sequence was detected in the protein sequence data bank, but no homogeneous sequence was found.     

Effect of Adding the Limiting Amino Acids to an Amino Acid Diet Simulating Rice Protein on the Conversion of Tryptophan to Nicotinamide in Rats

The effect of amino acid composition on the conversion ratio of tryptophan to nicotinamide was investigated. The ratio in the group fed with an amino acid diet simulating rice protein was around 2.5%. This ratio was statistically decreased by the addition of the limiting amino acids, except for tryptophan, and increased by the addition of all the limiting amino acids, including tryptophan. The composition of amino acids proved to greatly affect the conversion ratio.     

Isolation and Identification of the 3-Hydroxy-5-hydroxymethyl-pyridinium Compound as a Novel Advanced Glycation End Product on Glyceraldehyde-related Maillard Reaction

Glyceraldehyde (200 mM) and N^α-acetyllysine (100 mM) were incubated in 0.2 M sodium phosphate buffer (pH 7.4) at 37°C for a week. A major compound, glyceraldehyde-related Maillard reaction product, was purified from the reaction mixture using reverse phase (ODS)-HPLC. It was identified as 1-(5-acetylamino-5-carboxypentyl)-3-hydroxy-5-hydroxymethyl-pyridinium, named as GLAP (Glyceraldehyde derived Pyridinium compound), using NMR and MS analyses. It was suggested that GLAP as a novel advanced glycation end product (AGE) is one of the key compounds in the glyceraldehyde-related Maillard reaction.     

SNP discovery using Paired‐End RAD‐tag sequencing on pooled genomic DNA of Sisymbrium austriacum (Brassicaceae)

Single nucleotide polymorphisms SNPs are rapidly replacing anonymous markers in population genomic studies, but their use in non model organisms is hampered by the scarcity of cost‐effective approaches to uncover genome‐wide variation in a comprehensive subset of individuals. The screening of one or only a few individuals induces ascertainment bias. To discover SNPs for a population genomic study of the Pyrenean rocket (Sisymbrium austriacum subsp. chrysanthum), we undertook a pooled RAD‐PE (Restriction site Associated DNA Paired‐End sequencing) approach. RAD tags were generated from the PstI‐digested pooled genomic DNA of 12 individuals sampled across the species distribution range and paired‐end sequenced using Illumina technology to produce ~24.5 Mb of sequences, covering ~7% of the specie's genome. Sequences were assembled into ~76 000 contigs with a mean length of 323 bp (N₅₀ = 357 bp, sequencing depth = 24x). In all, >15 000 SNPs were called, of which 47% were annotated in putative genic regions based on homology with the Arabidopsis thaliana genome. Gene ontology (GO) slim categorization demonstrated that the identified SNPs covered extant genic variation well. The validation of 300 SNPs on a larger set of individuals using a KASPar assay underpinned the utility of pooled RAD‐PE as an inexpensive genome‐wide SNP discovery technique (success rate: 87%). In addition to SNPs, we discovered >600 putative SSR markers.     

Microtubule nucleation and organization in dendrites

Dendrite branching is an essential process for building complex nervous systems. It determines the number, distribution and integration of inputs into a neuron, and is regulated to create the diverse dendrite arbor branching patterns characteristic of different neuron types. The microtubule cytoskeleton is critical to provide structure and exert force during dendrite branching. It also supports the functional requirements of dendrites, reflected by differential microtubule architectural organization between neuron types, illustrated here for sensory neurons. Both anterograde and retrograde microtubule polymerization occur within growing dendrites, and recent studies indicate that branching is enhanced by anterograde microtubule polymerization events in nascent branches. The polarities of microtubule polymerization events are regulated by the position and orientation of microtubule nucleation events in the dendrite arbor. Golgi outposts are a primary microtubule nucleation center in dendrites and share common nucleation machinery with the centrosome. In addition, pre-existing dendrite microtubules may act as nucleation sites. We discuss how balancing the activities of distinct nucleation machineries within the growing dendrite can alter microtubule polymerization polarity and dendrite branching, and how regulating this balance can generate neuron type-specific morphologies.     

Depletion of JMJD5 sensitizes tumor cells to microtubule-destabilizing agents by altering microtubule stability

Microtubules play essential roles in mitosis, cell migration, and intracellular trafficking. Drugs that target microtubules have demonstrated great clinical success in cancer treatment due to their capacity to impair microtubule dynamics in both mitotic and interphase stages. In a previous report, we demonstrated that JMJD5 associated with mitotic spindle and was required for proper mitosis. However, it remains elusive whether JMJD5 could regulate the stability of cytoskeletal microtubules and whether it affects the efficacy of microtubule-targeting agents. In this study, we find that JMJD5 localizes not only to the nucleus, a fraction of it also localizes to the cytoplasm. JMJD5 depletion decreases the acetylation and detyrosination of α-tubulin, both of which are markers of microtubule stability. In addition, microtubules in JMJD5-depleted cells are more sensitive to nocodazole-induced depolymerization, whereas JMJD5 overexpression increases α-tubulin detyrosination and enhances the resistance of microtubules to nocodazole. Mechanistic studies revealed that JMJD5 regulates MAP1B protein levels and that MAP1B overexpression rescued the microtubule destabilization induced by JMJD5 depletion. Furthermore, JMJD5 depletion significantly promoted apoptosis in cancer cells treated with the microtubule-targeting anti-cancer drugs vinblastine or colchicine. Together, these findings suggest that JMJD5 is required to regulate the stability of cytoskeletal microtubules and that JMJD5 depletion increases the susceptibility of cancer cells to microtubule-destabilizing agents.     

Mechanism and regulation of DNA end resection in eukaryotes

The repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is initiated by nucleolytic degradation of the 5′-terminated strands in a process termed end resection. End resection generates 3′-single-stranded DNA tails, substrates for Rad51 to catalyze homologous pairing and DNA strand exchange, and for activation of the DNA damage checkpoint. The commonly accepted view is that end resection occurs by a two-step mechanism. In the first step, Sae2/CtIP activates the Mre11–Rad50–Xrs2/Nbs1 (MRX/N) complex to endonucleolytically cleave the 5′-terminated DNA strands close to break ends, and in the second step Exo1 and/or Dna2 nucleases extend the resected tracts to produce long 3′-ssDNA-tailed intermediates. Initiation of resection commits a cell to repair a DSB by HR because long ssDNA overhangs are poor substrates for non-homologous end joining (NHEJ). Thus, the initiation of end resection has emerged as a critical control point for repair pathway choice. Here, I review recent studies on the mechanism of end resection and how this process is regulated to ensure the most appropriate repair outcome.     

New Anthracene‐Fused Nonfullerene Acceptors for High‐Efficiency Organic Solar Cells: Energy Level Modulations Enabling Match of Donor and Acceptor

Two new nonfullerene small molecule acceptors (NF‐SMAs) AT‐NC and AT‐4Cl based on heptacyclic anthracene(cyclopentadithiophene) (AT) core and different electron‐withdrawing end groups are designed and synthesized. Although the two new acceptor molecules use two different end groups, naphthyl‐fused indanone (NINCN) and chlorinated INCN (INCN‐2Cl) demonstrate similar light absorption. AT‐4Cl with chlorinated INCN as end groups are shifted significantly due to the strong electron‐withdrawing ability of chlorine atoms. Thus, desirable V_oc and photovoltaic performance are expected to be achieved when polymer PBDB‐T is used as the electron donor with AT‐NC as the acceptor, and fluorinated analog PBDB‐TF with down‐shifted energy levels is selected to blend with AT‐4Cl. Consequently, the device based on PBDB‐TF:AT‐4Cl yields a high power conversion efficiency of 13.27% with a slightly lower V_oc of 0.901 V, significantly enhanced J_sc of 19.52 mA cm^?2 and fill factor of 75.5% relative to the values based on PBDB‐T:AT‐NC. These results demonstrate that the use of a new electron‐rich AT core, together with energy levels modulations by end‐group optimizations enabling the match with polymer donors, is a successful strategy to construct high‐performance NF‐SMAs.