This document is a comprehensive summary of all the chapters in Weinberg's The Biology of Cancer that must be read for the course Molecular Biology and Oncology in Leiden. This includes Chapters 1-15 entirely and parts of Chapter 16. Moreover, this document contains concepts discussed in workgroups...
Theme 1: Basic aspects of cells and the nature of
cancer
SSA1 Molecular Basis of Cancer
You can describe and explain:
The organization of DNA into chromatin
● Chromatin consists of DNA wrapped around a nucleosome bead. Nucleosomes in turn are
octamers of 4 copies of histone proteins (H2A, H2B, H3, and H4). Often H1 is also bound to
the nucleosome.
● N-terminal tails of the histone proteins project out of the nucleosome and can be modified
● Histone proteins are somewhat positively charged which cancels the negative charge of
phosphate groups in DNA.
What the ‘histone code’ means and how it is established
● Nucleosomes are made up of a histone octamer which have their N-terminals projecting out
of the nucleosomes that are sensitive to modifications.
● Histone code refers to the variation in histone species modifications. These variations and
alterations could for example affect how DNA is packaged around the histone and therefore
transcriptional accessibility.
● Reader proteins read histone modifications and recruit certain proteins that can alter the
state of chromatin.
The modifications of chromatin and its relation to transcription
● Modification of chromatin can affect the ability of a gene to be transcribed e.g.
heterochromatin vs euchromatin.
● Generally, euchromatin is more accessible and allows for gene transcription while
heterochromatin is denser and usually blocks access to transcription factors.
● This chromatin state is mainly determined by the modifications of histones.
, ● Phosphorylation: effect varies.
● Methylation: transforms chromatin into heterochromatin state because the methyl groups
recruit heterochromatin proteins and provides a binding site for them which makes the DNA
more densely packed and blocks access
● Acetylation: transforms chromatin into
euchromatin state because acetyl dampens the
positive charge of the histons, thereby making
the overall charge more negative and causing
repelling between DNA.
● Ubiquitylation: ubiquitin blocks the binding
spot for polymerases and transcription factors.
● Heterochromatin can also propagate to
neighboring chromatin.
● A transcription regulatory protein can recruit
writer proteins to insert modifications that can
be recognized by a reader protein. The reader
protein can subsequently activate the writer
protein to modify the nucleosome.
● This heterochromatin propagation can also be
prevented:
● The DNA contains so-called barrier sequences,
which are areas of DNA that attract barrier proteins.
Barrier proteins counteract the cascade of the
writer-reader complex. This can be achieved through:
● 1) Acetylation of lysine side chains, preventing
methylation, which is necessary for condensation, and
thus ending the cascade.
● 2) Tethering a region of chromatin to a fixed side (such
as the nuclear pore), forming a physical barrier that
stops the cascade.
● 3) Tight binding to upstream nucleosomes making
them resistant to heterochromatin spreading.
● 4) Recruiting highly active histone-modifying enzymes
that erase the histone marks required for the
heterochromatin spread.
The occurrence of CpG islands in vertebrate genomes
● CpG islands are DNA sequences in the DNA that can be methylated and oftentimes leads to
inactivation of a gene e.g. if a promoter is methylated.
How the methylation pattern of DNA is transferred to daughter cells
● If DNA is replicated the newly replicated strand is not methylated, producing a
hemi-methylated DNA strand.
, ● Maintenance methyltransferase proteins can recognize the hemi-methylated strand and
methylate the unmethylated strand to maintain the methylation patterns.
● Histone methylation can also be inherited but is less rigid and also has to be maintained by
the daughter cell for the effect to persist.
● Chromatin packaging can also be inherited
The characteristics of a promoter and the mechanisms by which a transcription initiation complex
with RNA polymerase is assembled on the promoter
● Promoters provide recognition and binding sequences for transcription factors so that a
complex can be formed to initiate transcription.
● Promoters are under control of DNA regulatory sequences and enhancers.
● Enhancers are DNA sequences that can bind transcription factors, and not RNA polymerase,
to guide the transcription factors to the promoter.
● The way in which enhancers achieve this is by looping the DNA, thereby bringing the factors
into closer proximity. In addition, looping stabilizes the DNA.
● Mediator proteins function as scaffolds which allow transcription factors to form a complex.
A technique by which the activity of a promoter can be studied
● siRNA can be used to specifically inhibit certain mRNAs. It is possible to inhibit
housekeeping proteins or tumor suppressor proteins to study the effect of their absence
and their role in cancer development.
, ● The reverse can also be done: in a cancer cell an overexpressed oncogene can be targeted to
study whether the development of the tumor can be slowed or halted by inhibition of
certain proteins.
● siRNA gene silencing is a quick working technique
● miRNAs are more like the natural occurring RNAi molecules and thus less specific, whereas
siRNAs are designed and thus have a more specific binding.
● The successful implementation of siRNA is monitored by Western Blotting; protein presence
should be decreased.
● Another control is direct assessment of quantities of mRNA.
The basic aspects of transcription initiation, transcription as well as the processing of transcripts
● Transcription initiation begins by the recognition of the promoter region via a recognition
sequence known as the TATA box. Thereafter, more transcription factors are recruited to
form a transcription complex
● The open reading frame determines the protein that is produced, the open reading frame in
turn is determined by the start (AUG) and stop codons (UAU, UAG, UGA).
● The pre-mRNA strand is then provided with a 5’-methyl cap via 1) a phosphatase that
removes a 5’-p, 2) guanyl transferase which adds a GMP through reverse 5’to5’ linkage, and
3) a methyltransferase which adds methyl groups to guanosine. The methyl cap facilitates
mRNA translocation to the cytoplasm
● Furthermore, a poly-A-tail is added for stability and to prevent degradation.
● While RNA is being transcribed, RNA-processing proteins move with RNA polymerase on its
tail. For example, the capping proteins travel on the tail to ensure immediate capping of the
newly synthesized strand.
● Furthermore, the polymerase strand is phosphorylated which attracts other processing
proteins. When the polymerase is finished it is dephosphorylated again and only then can
transcribe again.
● Alternative splicing is that a single pre-RNA can produce multiple different mRNAs e.g. by
the combination of exons that are included and the order in which exons are connected to
each other. Tumors often process RNA through alternative splicing.
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