Cell Structure and Genetic Control 67different mRNAs. An siRNA can be perfectly complementary
to a particular mRNA, forming an siRNA-mRNA duplex. In
this case, the RISC will prevent the mRNA from being trans-
lated by causing destruction of the mRNA. As a result, a single
siRNA can silence one particular mRNA. In contrast to siRNA,
most miRNA molecules are only partially complementary to
the mRNA molecules that they repress. The mechanism of this
repression is complex and appears to involve both impaired
translation of the mRNA and increased mRNA degradation. As
a result, the synthesis of the specific proteins is reduced but not
abolished. This repression contributes to the proper control of
many essential processes in the cell.
Scientists estimate that there are 700–1,000 different
miRNA molecules in the human genome. Separate genes code
for many of these, but others are derived from introns within
genes that code for proteins. In that case, when the pre-mRNA
is cut and the exons are spliced together to make an mRNA
( fig. 3.17 ), an intron removed in the process is processed into
an miRNA that regulates the mRNA.
However, one miRNA can regulate the expression of more
than one mRNA. This is possible because one miRNA can be
incompletely complementary to a number of different mRNA
molecules (from different genes), causing them to be silenced. In
this way, a single miRNA may silence as many as an estimated
200 different mRNA molecules. Scientists currently estimate
that at least 30% of human genes are regulated by miRNAs.
Scientists have discovered a few hundred different miRNA
molecules in humans and have generated libraries of miRNAs
to silence the expression of many genes. This can help in the
study of normal genetic regulation and may lead to medical
applications. For example, an miRNA that inhibits expres-
sion of a tumor suppressor gene can promote cancer, whereas
a different miRNA that represses an oncogene (which pro-
motes cancer) could have the opposite effect. In general, tumor
cells produce fewer miRNA molecules than normal cells, and
changes in the miRNA profile of metastatic cancer might be
used to determine the origin, aggressiveness, and most effec-
tive treatment of the cancer.
Scientists hope to use RNA interference medically to sup-
press the expression of specific genes, either abnormal genes
of the patient or the genes of infectious viruses. Although there
have been some notable successes reported in clinical trials,
and research is ongoing, at the time of this writing the thera-
peutic uses of miRNA remain in the future.although the number can be much larger—the gene for the pro-
tein “titin” contains 234 exons! Splicing together these exons in
different ways could produce many variations of the protein prod-
uct. The human proteome is thus much larger than the genome,
allowing tremendous flexibility for different functions.
Introns are cut out of the pre-mRNA, and the ends of the
exons are spliced, by macromolecules called snRNPs (pro-
nounced “snurps”), producing the functional mRNA that leaves
the nucleus and enters the cytoplasm. SnRNPs stands for small
nuclear ribonucleoproteins. These are small, ribosome-like
aggregates of RNA and protein that form a body called a spliceo-
some that splices the exons together.
RNA Interference
The 2006 Nobel Prize in Physiology or Medicine was awarded
for the discovery of RNA interference (RNA i ) , a regulatory
process performed by RNA molecules. In this process, cer-
tain RNA molecules that don’t code for proteins may prevent
specific mRNA molecules from being expressed (translated).
RNA interference is mediated by two very similar types of
RNA. One type is formed from longer double-stranded RNA
molecules that leave the nucleus and are processed in the
cytoplasm by an enzyme (called Dicer ) into short (21 to
25 nucleotides long) double-stranded RNA molecules called
short interfering RNA, or siRNA. The double-stranded RNA
is formed from either the transcription of a segment of two
complementary DNA strands, or from double-stranded RNA
produced by a virus inside the host cell. In this, RNA interfer-
ence is a mechanism to help combat the viral infection.
The other type of short RNA that participates in RNA inter-
ference is formed from longer RNA strands that fold into hairpin
loops that resemble double-stranded RNA. These form in the
nucleus and then are sent to the cytoplasm, where an enzyme
called Dicer cleaves the longer RNA into two strands. One of
these strands is the short (about 22 nucleotides long) microRNA
( miRNA ), which enters a particle called the RNA-induced
silencing complex ( RISC ). This single-stranded miRNA binds
by complementary base pairing within the RISC to a portion of
an mRNA, which thereby leads to suppressed translation of the
gene. This miRNA suppression appears to be relatively modest,
acting more as a fine-tuning mechanism than as an on/off switch.
Another type of RNA recently found to have regulatory
functions in human cells is circular RNA ( circRNA ). There
appear to be thousands of these, formed by splicing (through
head-to-tail covalent bonding) of exons from the same pre-
mRNA. Recent reports demonstrate that each circRNA mol-
ecule has numerous binding sites for copies of a particular
miRNA. Within a RISC particle, this binding serves as a
“sponge” to prevent the miRNA molecules from suppressing
the translation of their target mRNA molecules—they inhibit
the inhibitory miRNA. Because the functions of miRNA and
siRNA have been more thoroughly studied, however, the rest
of this section is devoted to these RNA forms.
There can be a range in the degree of complementary
base pairings between one siRNA or miRNA and a number of
| CHECKPOINTS
- Describe the appearance and composition of
chromatin and the structure of nucleosomes.
Comment on the significance of histone proteins.
6a. Explain how RNA is produced within the nucleus
according to the information contained in DNA.
6b. Explain how precursor mRNA is modified to produce
mRNA.