Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

432 Chapter 7: Control of Gene Expression
We have seen that although miRNAs and siRNAs are generated in slightly different
ways, they rely on the same proteins and seek out their targets in a fundamentally
similar manner. Because siRNAs are found in widespread species, they
are believed to be the most ancient form of RNA interference, with miRNAs being
a later refinement. These siRNA-mediated defense mechanisms are crucial for
plants, worms, and insects. In mammals, a protein-based system (described in
Chapter 24) has largely taken over the task of fighting off viruses.
RNA Interference Can Direct Heterochromatin Formation
The siRNA interference pathway just described does not necessarily stop with
the destruction of target RNA molecules. In some cases, the RNA interference
machinery can also selectively shut off synthesis of the target RNAs. For this to
occur, the short siRNAs produced by the Dicer protein are assembled with a group
of proteins (including Argonaute) to form the RITS (RNA-induced transcriptional
silencing) complex. Using single-stranded siRNA as a guide sequence, this complex
binds complementary RNA transcripts as they emerge from a transcribing
RNA polymerase II (Figure 7–77). Positioned on the genome in this way, the RITS
complex attracts proteins that covalently modify nearby histones and eventually
direct the formation of heterochromatin to prevent further transcription initiation.
In some cases, an RNA-dependent RNA polymerase and a Dicer enzyme are
also recruited by the RITS complex to continually generate additional siRNAs in
situ. This positive feedback loop ensures continued repression of the target gene
even after the initiating siRNA molecules have disappeared.
RNAi-directed heterochromatin formation is an important cell defense mechanism
that limits the spread of transposable elements in genomes by maintaining
their DNA sequences in a transcriptionally silent form. However, this same
mechanism is also used in some normal processes in the cell. For example, in
many organisms, the RNA interference machinery maintains the heterochromatin
formed around centromeres. Centromeric DNA sequences are transcribed
in both directions, producing complementary RNA transcripts that can basepair
to form double-stranded RNA. This double-stranded RNA triggers the RNA
double-stranded RNA
Argonaute and
other RISC proteins
siRNAs
Argonaute and
other RITS proteins
RISC
RITS
PATHWAY NOW FOLLOWS ONE OF
THOSE SHOWN IN Figure 7–76
RNA polymerase
HISTONE METHYLATION
DNA METHYLATION
TRANSCRIPTIONAL REPRESSION
Figure 7–77 RNA interference directed
by siRNAs. In many organisms, doublestranded
RNA can trigger both the
destruction of complementary mRNAs
(left) and transcriptional silencing (right).
The change in chromatin structure
induced by the bound RITS (RNAinduced
transcriptional silencing) complex
resembles that in Figure 7–45.