Current Genomics - Volume 7, Issue 5, 2006

Cytochromes P450 (P450s or CYPs) constitute a superfamily of heme-containing monooxygenases and have been shown to play a major role in both xenobiotic and endogenous metabolism. Thanks to the Human Genome Project, the current list of human CYPs should be exhaustive and so far 57 P450 encoding genes have been identified. To date, fif-teen of them, generally called "orphans" cytochromes P450, which were mainly identified by homology research between the sequences of known P450s and genomic sequences or ESTs (Expressed Sequence Tags) databases, are not fully char-acterized. However, tissue distribution, catalytic properties and physiological functions of these "novel P450s" are being analysed and partial results are already available for some of them, including CYP2 (CYP2A13, CYP2R1, CYP2S1, CYP2U1 and CYP2W1), CYP3 (CYP3A43) and CYP4 (CYP4A22, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1) family members. In this review, we present some of the current data characterizing these P450s and discuss their potential involvement in xenobiotic toxicity and carcinogenesis, as well as their physiological relevance in pathology susceptibility.

Despite substantial recent progress, gene structural prediction remains a challenging problem in bioinformatics. The importance of a detailed understanding of gene splicing can be underlined by noting that ∼10-15% of human genetic diseases are caused by mutations that affect splice junctions. We briefly introduce the problem, mention the existing ap-proaches to gene structural annotation and provide overview of current methods. In particular, this paper explains why homology-based gene structural prediction appears to be more difficult then it might seem. The problem of splice sites (SSs) sensor design is overviewed with rigorous comparison of key designs. Finally, a discussion of methods in ab initio gene structural prediction is accompanied by an extensive comparative performance study. We make certain conclusions regarding the current state of the art and try to speculate about future research directions. Applications used to evaluate performance characteristics for various gene structural prediction programs are available online at http://www. wyomingbioinformatics.org/∼achurban/.

Gene expression profiling of a number of distinct brain regions under different behavioral and biological states was analyzed using DNA microarray technology. These included hippocampal development, aging process, environ-mental enrichment, fear conditioning, and calorie restriction. Our results identified numerous genes and signal pathways that may play critical roles in learning and memory, brain aging and longevity. Furthermore, chemical genetic approach combined with gene expression profiling analysis was applied to study the molecular mechanisms that contribute to brain dysfunction including Alzheimer's diseases, neuronal degeneration and brain aging. These studies not only revealed that a number of genes and signal pathways may have participated in the pathological processes of the brain diseases, but also contributed to the identification of therapeutic targets for drug screening and development.

Nitric oxide (NO) is a potent cell signaling and effector molecule that participates in numerous physiological and pathophysiological events in a variety of cell types and tissues. NO derived from all major isoforms of NO synthase can S-nitrosylate cysteine thiols in target proteins, potentially altering their functional activities in a redox-dependent, cGMP-independent manner. Formation of protein S-nitrosocysteine adducts appears to occur through multiple pathways. Emerging evidence suggests that S-nitrosylation is a specific, reversible and regulated covalent post-translational modifi-cation that modulates diverse biological and physiological functions. In addition to altering protein activity, localization and stability, S-nitrosylation participates in the control of cellular metabolism, apoptosis, protein-protein interactions, transcription factor function, ion channel activity and cellular redox balance. Increasingly sophisticated proteomic ap-proaches used in various cell types and tissues have identified S-nitrosylation of proteins of virtually all major classes, in-cluding cytoskeletal proteins, chaperones, proteins of the translational and transcriptional machinery, vesicular transport and signaling. S-nitrosylation has also been shown to regulate the NO synthase isoforms themselves, reversibly inhibiting endothelial NO synthase activity and feedback inhibiting PARP-1, a transactivator of inducible NO synthase. Imbalances in NO metabolism and dysregulated S-nitrosylation have been implicated in a growing list of human diseases, such as neurodegenerative disorders, endotoxemic shock and insulin resistance. Here we review the key discoveries and directions in this field, including the role of S-nitrosylation as a potential therapeutic target in specific human diseases.

DNA double-strand breaks (DSBs) are a common form of DNA damage and double-strand break rejoining is a fundamental mechanism of genome protection to prevent chromosomal fragmentation, translocation and deletions. DSBs may be induced by exogenous agents, such as ionizing radiation, but also occur spontaneously during cellular processes e.g. in the rearrangement of gene segments during V(D)J [variable (V), diversity (D), joining (J)] recombination. The ge-nomic instability resulting from incorrectly repaired DSBs can lead to carcinogenesis, while unrepaired may carry on even to cell death. To repair this potentially lethal damage cells developed several different types of repair act on the DSBs e.g. homologous recombination repair (HRR), non-homologous DNA end joining (NHEJ), and single-strand annealing (SSA).The most essential in mammalian cells is NHEJ, whereas HRR and SSA significantly contributes to DSBs repair in lower eukaryotes. At least six distinct proteins are known to be required for NHEJ, including Ku70, Ku80, DNA-PKcs, XRCC4, DNA ligase IV, and Artemis. In this review we highlight classical and up-to-date aspects and present understanding of the molecular mechanisms of NHEJ in the maintenance of genome integrity.

Integrins are composed of a variety of binding subunits that are responsible for interacting with the extracellu-lar matrix and intracellular signaling pathways. Among their various functions, integrins have the ability to augment cellu-lar adhesion, influence cytoskeletal architecture, activate tyrosine kinase and affect cell survival. Many investigations have demonstrated a correlation between the regulation of integrin expression and tumor invasiveness and proliferation. Integrins affect transcription factors Twist and HoxD3, epigenetic regulation, matrix metalloproteinases, insulin-like growth factors, integrin-linked kinases and adherens junctions, which are all important components of tumorigenicity. Cancer cells modify their functional genomic composition thereby altering integrin expression. Understanding the rela-tionship between integrin expression and tumor activities could provide an important strategy for cancer treatment.