Helicase Domain Containing Proteins in Human Disorders Pp. 305-324
Adayabalam S. Balajee and
Colette ApRhys
Comparative Genomic Hybridization: A Valuable Tool for Genome-Scale Analysis of Rodent Cancer Models Pp. 325-336
R. Kappler and H. Scherthan
SNARE Proteins - From Membranes to Genomes Pp. 337-348
Michal Linial
Mitochondrial Contributions to Aging in the Nematode Caenorhabditis elegans Pp. 349-356
Naoaki Ishii, Kiyoshi Kita
and Phil S. Hartman
Turner Syndrome : How Is It Made Up? Pp. 357-377
Tsutomu Ogata
Transcriptional Regulation in Mammalian Pituitary Development and Disease Pp. 379-398
Kyle W. Sloop, Gretchen E.
Parker and Simon J. Rhodes
Micro Arrays and Biochips: Applications and Potential in Genomics and Proteomics Pp. 399-415
Tuan Vo-Dinh and Minoo Askari
[Back to top] Helicase Domain Containing Proteins in Human Disorders
Adayabalam S. Balajee and Colette ApRhys
Helicases are enzymes that unwind
DNA-DNA and RNA-DNA duplexes play important roles in many DNA metabolic
activities like replication, transcription, recombination and repair. The
molecular link between helicases and genomic stability has become stronger by
recent studies indicating that the genes responsible for certain human
degenerative disorders such as Werner syndrome (WS), Bloom syndrome (BS) and
Rothmund-Thomson syndrome (RTS) encode for helicase domain containing proteins
(HDPs) homologous to bacterial RecQ super family of helicases. The patients
suffering from these disorders show many signs that are suggestive of
accelerated aging at an early adulthood. Some of the features include atrophy
of the skin, graying of the hair, cataracts, diabetes and osteoporosis.
Additionally, symptoms of accelerated aging and genomic instability have also
been noticed in xeroderma pigmentosum (XP) and Cockayne syndrome (complementation
group B) patients. The gene products of XP complementation groups B and D are
helicases and they play dual roles both in nucleotide excision repair and RNA
polymerase II transcription. The CSB protein with a remarkably conserved
helicase domain is homologous to yeast SWI/SNF family of proteins that have
regulatory roles in transcription, chromosome stability and DNA repair.
Although genomic instability is a common feature of helicase disorders,
elucidation of precise biological function(s) of helicases is critical for
defining the molecular basis for diverse clinical symptoms of these patients.
Recent studies have characterized the preferred DNA substrates for RecQ
helicases and also identified the interaction of HDPs with a number of proteins
involved in DNA replication, transcription, recombination and repair. These
interactions have given great insights into functional complexities of
helicases. This review deals with our current knowledge on the diverse
biological functions of HDPs and their collective role in the maintenance of
genomic stability.
[Back to top] Comparative Genomic Hybridization: A Valuable Tool for Genome-Scale Analysis of Rodent Cancer Models
R. Kappler and H. Scherthan
Comparative genomic in situ hybridization (CGH) studies have marked regions of unbalanced genomic alterations in a variety of human solid and hematological malignancies. Subsequent molecular analysis helped to pinpoint genes contributing to tumorigenic development and progression. CGH has since become a routine tool in molecular diagnostics and cancer research. Since mice and rats represent major model systems for human malignancies, CGH was soon adapted for tracing DNA copy number changes in experimental rodent tumor genomes. A stronghold of this approach is the potential transfer of information to the human situation by use of comparative maps of mouse and rat, and the human genome. This allows for an evaluation and validation of rodent tumor models at the genomic level. This review will illuminate the insights obtained by CGH analysis of rodent tumor genomes and the comparative transfer of this information between rodents and human.
[Back to top] SNARE Proteins - From Membranes to Genomes
Michal Linial
The function and the organization of eukaryotic cells require directional transport of vesicles between compartments. This sort of membrane flow relies on the presence of docking and fusion machinery. The core of this machinery is a protein complex composed of syntaxin, SNAP-25 and VAMP, collectively termed SNAREs. A correct interaction among SNARE prototypes is essential for fruitful docking and fusion. Analysis of large-scale sequencing projects reveals that each of the SNARE proteins (syntaxin, SNAP-25 and VAMP) is a member of a large protein family that is represented in every eukaryotic genome. The diversity among the three SNARE prototypes allows an enriched combinatorial make-up to meet a wide range of cellular demands for secretion.
Herein, we discuss the diversity in SNARE proteins from a
genomic perspective. We combine information from large-scale sequence data with
structural and functional classifications of SNAREs. Using a sequence-based
automated protein classification tool, we expose weak but significant
connections among all three SNARE protein clusters. These connections define a
local evolutionary network within the protein universe. Genomic data allows us
to identify classical SNAREs as well as their remote evolutionary relatives. We
focus on the SNARE representatives from human and plant genomes to discuss the
source of complexity and specificity for docking and fusion in a eukaryotic
cell. How many of the potential SNARE combinations are indeed valid in vivo,
and to what extent does each combination specify a biochemical and biophysical
unique entity, is yet to be experimentally determined.
[Back to top] Mitochondrial Contributions to Aging in the Nematode Caenorhabditis elegans
Naoaki Ishii,
Kiyoshi Kita and Phil S. Hartman
Free radicals and their sequelae figure prominently in
cellular and organismal aging. Generated primarily in mitochondria as unwanted
products of oxidative phosphorylation, free radicals induce a wide variety of
damage that compromises molecular, cellular and organismal integrity. The
free-living nematode Caenorhabditis elegans has been employed widely to explore
the genetics of aging. One extremely successful approach has been to isolate
mutants that extend life span. Conversely, genetic analyses of mutants that
shorten life span have also provided insights into aging as it occurs in wild
type. In this review we focus on three such "aging" mutants of C.
elegans (mev-1, gas-1 and clk-1). Although isolated in different laboratories
and using different selection criteria, all three affect aging by perturbing
mitochondrial structure and/or function. gas-1 encodes a subunit of complex I,
one of the five membrane-bound mitochondrial complexes that comprise the
electron transport system. Originally isolated because they are hypersensitive
to volatile anesthetics, gas-1 mutants were subsequently found to be
hypersensitive to oxidative stress, presented in the form of either hyperoxia
or methyl viologen. mev-1 encodes a subunit of complex II and was initially
studied on the basis of its hypersensitivity to oxidative stress. Mutations in
this gene confer a variety of interesting phenotypes, including precocious
aging, hypermutability, abnormal mitochondrial structure, compromised DNA
repair capacity and increased endogenous levels of free radicals. clk-1 encodes
a protein homologous to the yeast coq7/cat5 gene product. clk-1 mutations
result in reduced rates of certain developmental and behavioral phenomena as
well as in an extended life span. In yeast, coq7/cat5 mutants were reported to
be defective in respiration due to a deficiency in the biosynthesis of
ubiquinone. It has been hypothesized that the involvement of clk-1/coq7/cat5 in
ubiquinone biosynthesis is regulatory because clk-1 mutants show normal rates
of mitochondrial respiration. The phenotypes of each of these three mutants
will be presented, with emphasis on how they provide information about the
normal aging process.
[Back to top] Turner Syndrome : How Is It Made Up?
Tsutomu Ogata
Turner syndrome is a well defined sex chromosomal disorder
characterized by short stature, characteristic somatic stigmata, and gonadal
dysgenesis. In this review, I summarize recent progress in the clarification of
genetic mechanisms involved in the development of clinical features. The
essence is as follows: (1) Short stature is primarily ascribed to loss of SHOX
cloned from the short arm pseudoautosomal region and GCY postulated between
DYZ3 and DYS11 in the proximal part of Yq, in addition to non-specific growth
disadvantage caused by chromosome imbalance. (2) Skeletal features such as
short matacarpals, cubitus valgus, Madelung deformity, high arched palate, and
short neck are primarily attributable to SHOX haploinsufficiency, with
expressivity in the limb and faciocervical regions being influenced by gonadal
function status and the presence or absence of the lymphogenic gene,
respectively. (3) Soft tissue features such as webbed neck and lymphedema and
visceral features such as aortic coarctation and horseshoe kidney appear to be
due to haploinsufficiency of the lymphogenic gene postulated between DMD and
MAOA in the proximal Xp region and between PABY and DYS255 in the distal Yp
region. (4) Gonadal dysgenesis is explained by pairing failure of homologous
chromosomes in meiocytes that are genetically destined to develop as oocytes,
rather than by the dosage effect of an X-linked gene(s). In addition, the
underlying factors for the extreme prenatal lethality, cognitive dysfunction,
mental retardation, gonadal tumors, and immune-related diseases are discussed.
[Back to top] Transcriptional Regulation in Mammalian Pituitary Development and Disease
Kyle W. Sloop, Gretchen E.
Parker and Simon J. Rhodes
The pituitary gland is a complex endocrine organ secreting
hormones that regulate a wide array of vertebrate physiological processes,
including growth, lactation, metabolic homeostasis, reproduction, water
balance, and the stress response. In the mature organ, specialized cells that
have a common origin in the early ectoderm release their characteristic
products into the bloodstream. Together, the embryological processes that
commit the hormone-secreting cells to their specific fates and the clinical and
agricultural relevance of understanding pituitary function have defined
pituitary development as an excellent model system for the study of the genetic
cascades that guide cell determination and differentiation. Recently, many
genes that regulate pituitary development have been identified. These genes
encode transcription factors and signaling proteins and often are expressed in
temporally controlled, pituitary-specific or pituitary-restricted patterns.
Further, dominant and recessive mutations in these genes are associated with
compound pituitary diseases in human patients and animal models. The advance of
genome projects will facilitate approaches to understand the genetic mechanisms
that regulate the activation of pituitary regulatory genes and to discover how
the function of the encoded transcription factors is precisely regulated by
intrinsic and extrapituitary signals. Gene array and differential screening
approaches will enable the identification of direct and downstream target genes
of pituitary transcription factors. Protein interaction screens will identify
regulatory proteins required for pituitary gene control. Characterization of
the pathways that coordinate pituitary development will direct treatment of
pediatric and adult pituitary diseases, guide genetic counseling of families
with hereditary conditions affecting the pituitary, and may allow embryonic
manipulation to improve productivity in the meat industry.
[Back to top] Micro Arrays and Biochips: Applications and Potential in Genomics and Proteomics
Tuan Vo-Dinh and Minoo Askari
This report provides an overview of the development and applications
of DNA-based microarrays and biochip technology in genomics. DNA microarrays
and biochip technologies are having a significant impact on a wide variety
of areas in genomic research. Many fields, including gene discovery, drug
discovery, toxicological research, and medical diagnostics, will benefit from
the use of DNA micro array and biochip technologies. High-density micro array
chips with relatively large detection systems are useful in the research laboratory
for monitoring the expression of large numbers of genes in parallel. On the
other hand, small and inexpensive integrated biochips that combine probe arrays
with sensor microchips are most suitable for medical diagnosis at the site-of-care.