BIOL 200 Lecture Notes - Nuclear Pore, Lysine, Dosage Compensation

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6 Apr 2012
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Naveen Sooknanan McGill Fall 2011
1
Chromatin Modification:
As we have learned before, DNA does not exist “naked” in the cell. It undergoes
extensive wrapping to form chromatin in the mitotic phase
Through associations with histones 1-4, DNA is wrapped into higher order
nucleosomes
These nucleosomes can undergo further folding into 30nm fibers, 300nm
fibers, 700nm fibers and eventually 1400nm chromatin fibers
While DNA is normally found in its wrapped up form, it must be unwound in order for protein
factors involved in transcription to bind to the DNA and carry out transcription
Modification in chromatin structure severely affects gene expression
(transcription) levels
Unwinding of the chromatin facilitates binding of transcription factors
thus increasing the rate of transcription
This unwinding can be carried out by a series of proteins and
complexes, including histone modifying enzymes, chromatin
remodelling complexes and components of RNA Polymerase II
Discovery of chromatin unwinding began with work on Saccharomyces
cerevisiae (baker’s yeast)
Baker’s yeast exists in two states: a diploid state (2 sets of chromosomes) and a haploid
state (1 set of chromosomes)
o Yeast likes the haploid state and spends most of its time like this
During the haploid phase, one yeast cell can be either an a or α mating type
o The mating type is determined by three genetic loci, positions on the chromosome
(chromosome III to be specific), and their
expression
HMLα and HMLa are two mating type loci located on the
telomeric ends of the chromosome
o These genes must be silenced (i.e. must not be
transcribed) otherwise the cell would be diploid and would not mate
The MAT locust (mating locust) is located in the middle of the chromosome and is the
only one expressed
By complex endonucleic activity, HMLα and HMLa are brought to the MAT region
where they can be expressed
The cell can only mate when it is in haploid state and it contains α and a in its mating
locust
Certain sequences of the yeast chromosome around the HML loci contain specific
silencer sequences which somehow code for the transcriptional repression of these
regions
Transcriptional repression through silencer sequences is not limited to mating loci; it can be seen
in the blocking of expression of tRNA genes (done by Pol III) as well as telomeric regions of
other chromosomes
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Naveen Sooknanan McGill Fall 2011
2
We now know that histone wrapping plays a huge role in transcriptional repression
through interaction of various factors with these silencer sequences
The factors involved in activating the silencing process of the mating type loci were identified
through genetic screening
RAP1 is a protein involved in binding to specific silencer sequences
as well as repetitive sequences found on telomeric regions of the
chromosome
SIR1 (silent information regulator 1) cooperates with RAP1 by
binding to it and allowing other factors to recognize the resulting
complex
SIR3 and 4 then recognize this complex and bind to the silencing
region, causing recruitment of another factor
SIR2 then binds to SIR4 and carries out a deacetylase function on the histone tails which
are attached to the DNA
o Histone tails normally carry a net positive charge and are thus capable of
interacting with the phosphate group of the DNA backbone, thus causing this
wrapping effect
o While acetylated DNA is loose because it carries a neutral charge, SIR2 takes the
removes these acetyl groups, which re-wraps the DNA/histone structure by
renewing this positive charge on the histone tails
These histone tails are not hypoacetylated (less acetyl groups)
SIR3 and 4 can recognize these hypoacetylated tails and form even larger complexes by
recruiting more SIR2 and causing further de-acetylation
o This spreads the wrapping effect all over the sequence to be silenced, effectively
stopping any transcription from happening
This method effectively shuts down various regions of the chromosome containing
silencer sequences or telomeric repeats
SIR3 has the specific function of co-localizing with telomeric DNA
o When the cell is stained in such a way as to
only reveal the telomeres, it can be seen
that SIR3 proteins are capable of binding to
these telomeric repeat regions through
certain kinds of microscopy
Transcriptional repressors (opposite to transcriptional activators we have discussed before) are
DNA binding factors which may act through histone deacetylation complexes (HDACs)
As stated before, histone tails (particularly the N terminal tails) are positively charges and
are capable of electrostatically interacting with the phosphate on the backbone of the
DNA
When this happens, the DNA wraps up and transcription
factors such as TBP are unable to bind to the TATA box
o Thus the pre-initiation complex in transcription
cannot be formed on hypoacetylated regions of the
chromosome
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