Chemical approaches toward understanding base excision DNA repair

Despite the importance of DNA repair in protecting the genome, the molecular basis for damage recognition and repair remains poorly understood. In the base excision repair pathway (BER), DNA glycosylases recognize and excise damaged bases from DNA. This review focuses on the recent development of chemical approaches that have been applied to the study of BER enzymes. Several distinctive classes of noncleavable substrate analogs that form stable complexes with DNA glycosylases have recently been designed and synthesized. These analogs have been used for biochemical and structural analyses of protein—DNA complexes involving DNA glycosylases, and for the isolation of a novel DNA glycosylase. An approach to trap covalently a DNA glycosylase-intermediate complex has also been used to elucidate the mechanism of DNA glycosylases.     

Agents that target telomerase and telomeres

Telomeres are guanine-rich regions that are located at the ends of chromosomes and are essential for preventing aberrant recombination and protecting against exonucleolytic DNA degradation. Telomeres are maintained by telomerase, an RNA-dependent DNA polymerase. Because telomerase is known to be expressed in tumor cells, which concurrently have short telomeres, and not in most somatic cells, which usually have long telomeres, telomerase and telomere structures have been recently proposed as attractive targets for the discovery of new anticancer agents. The most exciting current strategies are aimed at specifically designing new drugs that target telomerase or telomeres and new models have been formulated to study the biological effects of inhibitors of telomerase and telomeres both in vitro and in vivo.     

Applications of DNA shuffling to pharmaceuticals and vaccines

DNA shuffling is a practical process for directed molecular evolution which uses recombination to dramatically accelerate the rate at which one can evolve genes. Single and multigene traits that require many mutations for improved phenotypes can be evolved rapidly. DNA shuffling technology has been significantly enhanced in the past year, extending its range of applications to small molecule pharmaceuticals, pharmaceutical proteins, gene therapy vehicles and transgenes, vaccines and evolved viruses for vaccines, and laboratory animal models.     

Toward the development of DNA vaccines

DNA vaccination has proved to be a generally applicable technology in various preclinical animal models of infectious and noninfectious disease and several DNA vaccines have now entered phase I human clinical trials. It is too early to predict the effectiveness of DNA vaccines in humans and whether improved formulations of DNA vaccines will be required but several lines of investigation have suggested ways in which DNA vaccines may be improved, such as increases in expession, facilitation of DNA targeting or uptake, and enhancement of immune responses.     

Vicious circles: a mechanism for yeast aging

The past year has confirmed the great potential of the yeast Saccharomyces cerevisiae as a model to study aging. Ground breaking papers have revealed similarities between aging in yeast and in mammals, and have identified genetic instability of the ribosomal DNA array as the first known cause of aging in yeast cells.     

GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins

Cell biology depends on the interactions of macromolecules, such as protein—DNA, protein—protein or protein—nucleotide interactions. GTP-binding proteins are no exception to the rule. They regulate cellular processes as diverse as protein biosynthesis and intracellular membrane trafficking. Recently, a large number of genes encoding GTP-binding proteins and the proteins that interact witht these molecular switches have been cloned and expressed. The 3D structures of some of these have also been elucidated     

Insights into the mechanisms of homologous recombination from the structure of RuvA

The recent structure determination of RuvA has provided the first insights into the structural basis for its interaction with Holliday junction DNA. Multiple copies of a helix-hairpin-helix motif which line the four grooves between the monomers in the tetrameric structure are thought to be involved in the interaction of the protein with its DNA target. This suggests that the four arms of the junction are held by RuvA in a fourfold symmetric arrangement and has fuelled ideas on the way in which components of the Ruv complex combine to catalyse the process of homologous recombination     

Out of Africa? What do genes tell us?

Genetic diversity patterns in nuclear versus mitochondrial systems and in low versus high mutation rate systems do not support the hypothesis of a recent African origin for all of humanity following a split between Africans and non-Africans 100,000 years ago, nor do genetic distance data. Geographical analyses of nuclear and mitochondrial gene trees do not support the hypothesis of a recent global replacement of humans coming out of Africa, although a local replacement event in Europe is indicated by these analyses and recent studies on Neandertal DNA. The gene tree analyses instead indicate that genetic interchanges have ensured that all of humanity has evolved as a single evolutionary lineage with no major splits.     

Remembrance of things past: maintaining gene expression patterns with altered chromatin

Eukaryotic organisms have evolved mechanisms to stably preserve the gene expression patterns that determine cell fate. Recent advances have been made in understanding the DNA sequences and protein factors required to propagate gene activation or silencing. These studies suggest that, after gene activity states are selected during development, maintenance protein complexes provide a molecular memory of those states by altering a local domain of chromatin structure.     

Antifreeze proteins

Antifreeze proteins comprise a structurally diverse class of proteins that inhibit the growth of ice. Recently, new AFP types have been discovered; more active AFPs have been isolated; antecedents have been recognized supporting the notion of recent, multiple origins; and detailed structures have emerged leading to models for their adsorption to ice     

Mechanisms of DNA bending

Genome packaging and gene regulation require DNA bending. Recent developments in the elucidation of the mechanisms involved in DNA bending include new X-ray structures (most notably that of the mammalian nucleosome) wherein DNA is bent, controversy surrounding interpretation of DNA-bending experiments with basic-leucine zipper proteins, studies of electrostatic effects in DNA bending, and the design of artificial DNA-bending ligands.     

Infection-related development in the rice blast fungus Magnaporthe grisea

Recent developments have been made in the identification of signal transduction pathways and gene products involved in the infection-related development of the rice blast fungus, Magnaporthe grisea. It has been established that cAMP-dependent and MAP kinase-mediated signaling are both critical for appressorium morphogenesis and function. These signaling pathways may act downstream of hydrophobin-mediated surface sensing by the growing germ tube. Several genes have been identified that are required for invasive growth of M. grisea including genes that allow adaptation of fungal metabolism to growth within plant tissues.     

Artificial dinuclear phosphoesterases

Many elegant dinuclear transition metal and lathanide complexes that efficiently hydrolyze phosphate esters including RNA and DNA have been reported recently. In most cases, the dinuclear complexes are much more reactive than the corresponding mononuclear metal complexes. Furthermore, structural and kinetic data indicate that substantial rate acceleration for phosphate diester cleavage is obtained by bridging the dinuclear metal centers with the two phosphoryl oxygens. Interestingly, such bridging structures have recently been implicated in several metalloenzyme catalyzed phosphate hydrolyses.     

Heterocyst formation in Anabaena

Heterocystous cyanobacteria grow as multicellular organisms with a distinct one-dimensional developmental pattern of single nitrogen-fixing heterocysts separated by approximately ten vegetative cells. Several genes have been identified that are required for heterocyst development and pattern formation. A key regulator, HetR, has been recently shown to be aserine-type protease.     

Human evolution and the mitochondrial genome

The use of mitochondrial DNA (mtDNA) continues to dominate studies of human genetic variation and evolution. Recent work has re-affirmed the strict maternal inheritance of mtDNA, yielded new insights into the extent and nature of intra-individual variation, supported a recent African origin of human mtDNA, and amply demonstrated the utility of mtDNA in tracing population history and in analyses of ancient remains.     

Inertial vestibular coding of motion: concepts and evidence

Central processing of inertial sensory information about head attitude and motion in space is crucial for motor control. Vestibular signals are coded relative to a non-inertial system, the head, that is virtually continuously in motion. Evidence for transformation of vestibular signals from head-fixed sensory coordinates to gravity-centered coordinates have been provided by studies of the vestibulo-ocular reflex. The underlying central processing depends on otolith afferent information that needs to be resolved in terms of head translation related inertial forces and head attitude dependent pull of gravity. Theoretical solutions have been suggested, but experimental evidence is still scarce. It appears, along these lines, that gaze control systems are intimately linked to motor control of head attitude and posture.