ASH-SAP American Society of Hematology Self-Assessment Program
Preface
Advances in recombinant DNA technology over the past several de cades have
substantially altered our view of biologic pro cesses and have immediate relevance to our understanding of both normal hematopoietic cell function and
hematologic pathology
. A complete review of molecular ge ne tics is beyond the
scope of this chapter, but it is intended as a review of the concepts of the molecular biology of the gene, an introduction to epigenet ics and genomics, an
outline of noncoding RNAs, concepts relevant for immunotherapeutic treatment approaches, and an explanation of the terminology necessary for understanding the role of molecular biology in breakthrough discoveries
. Emerging
diagnostic and therapeutic approaches in hematology are reviewed
. The concepts outlined in the following sections also are illustrated in Figure 1-1; in addition, boldface terms in the text are summarized in the glossary at the end of
this chapter
. Several examples of how these concepts and techniques are applied
in clinical practice are included
Anatomy of the gene
DNA is a complex, double- stranded molecule composed of nucleotides
. Each
nucleotide consists of a purine (adenine or guanine) or pyrimidine (thymine
or cytosine) base attached to a deoxyribose sugar residue
. Each strand of DNA
is a succession of nucleotides linked through phosphodiester bonds between
the 5′ position of the deoxyribose of one nucleotide and the 3′ position of the
sugar moiety of the adjacent nucleotide
. The two strands are connected through
hydrogen bonds between strict pairs of purines and pyrimidines; that is, adenine
must be paired with thymine (A- T) and guanine must be paired with cytosine
(G- C). This is known as Watson- Crick base pairing. Consequently, the two
strands of DNA are said to be complementary, in that the sequence of one
strand determines the sequence of the other through the demands of strict base
pairing. The two strands are joined in an antiparallel manner so that the 5′ end
of one strand is joined with the 3′ end of the complementary strand. The strand
containing the codons for amino acid sequences is designated as the sense strand,
whereas the opposite strand that is transcribed into messenger RNA (mRNA) is
referred to as the antisense strand.
Structure of the gene
DNA dictates the biologic functions of the organism by
the flow of genetic information from DNA to RNA to
protein
. The functional genetic unit responsible for the production of a given protein, including the elements that control the timing and the level of its expression, is termed a
gene
. The gene contains several critical components that
determine both the amino acid structure of the protein it
encodes and the mechanisms by which the production of
that protein may be controlled
. The coding sequence,
which dictates protein sequence, is contained within
Flow of genetic information
Transcription
RNAs are mostly single-stranded molecules that differ
from DNA in two ways: by a sugar backbone composed
of ribose rather than deoxyribose, and by containing the
pyrimidine uracil rather than thymine
. The first step in
the expression of protein from a gene is the synthesis of
a pre-messenger RNA (pre-mRNA). The transcription of pre-mRNA is directed by RNA polymerase II,
which in conjunction with other proteins generates an
RNA copy of the DNA sense strand
. The introns are then
removed by a complex process called mRNA splicing
.
This process involves the recognition of specific sequences
on either side of the intron which allow its excision in
a precise manner that maintains the exon sequence
. The
mRNA may then undergo modifications at the 5′ and
3′ ends (capping and polyadenylation, respectively).
Although RNA splicing is largely restricted to the nucleus,
it also can occur in the cytoplasm of platelets and neutrophils activated by external stimuli .
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