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Summary SSA1 Molecular Basis of Cancer
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Summary and WG answers of SSA1 Molecular Basis of Cancer of the course MBO (molecular biology and oncology) at Leiden University.
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SSA1 Molecular Basis ofCancer
Chapter 1 Weinberg
Mutations are responsible for changes in genes. The most common gene variant is called the
wild type. The collection of all alleles present in the genomes in a species is called the gene
pool. The majority of the DNA consists of junk DNA which is non-coding. Only 1.5% is
actually encoding proteins. Mutations in junk DNA have basically no effect on the phenotype
and are therefore called neutral mutations (not advantageous, nor disadvantageous).
Selected mutations do have an effect on the phenotype.
Genetic polymorphisms are the inter-individual, often functionally silent, differences in the
DNA sequence that make each human genome unique. The 3.5% of the DNA that has a
function behaves differently from the junk DNA. There are way less mutations in the coding
part as mutations often lead to loss of function. This even leads to a lot of similarity in genes
between species (genetic conservation). The variability is thus mainly in the junk DNA.
The karyotype is the chromosomal array. Each gene is located at a specific site, the genetic
locus. The autosomes are the non-sex chromosomes. The Barr body is the inactivated X-
chromosome. The Y chromosome has way less genes than the X chromosome.
1.4 Chromosomes are altered in most types of cancer cells
There can be aneuploidy which means that there is an abnormal amount of chromosomes.
This often occurs in cancer and is a sign of general chaos.
There can be duplications or deletions, inversions of parts of chromosomes and
translocations between chromosomes (reciprocal translocation). Homogenously staining
regions are a large number of extra copies of a part of a chromosome that are fused. The
acquisitions of extra copies of certain parts of the chromosome or loss of others creates a
,genetic configuration that can benefit cancer cells. The abnormal chromosomes can be
detected with in situ hybridizations. A segment can also be cleaved out, replicated and be
replicated many times leading to double minutes. This all leads to gene amplification.
Interstitial deletions occur when there is a deletion in the middle of a chromosome and the
flanking regions are now fused.
1.5 Mutations causing cancer occur in both the germ line and
the soma
Somatic mutations can, however, not be transmitted from generation to generation. Somatic
mutations can be very advantageous for cell growth and division leading to many clones with
the same mutation.
1.6 Genotype embodied in DNA sequences creates phenotype
through proteins
Proteins can have many functions. They can be a part of the cytoskeleton, can be secreted
to form the ECM, can be enzymes that mediate the intermediary metabolism, can lead to cell
motility, can convey signals (also between cells) which is called transduction.
Post-translational modification can also lead to different function of the protein. This leads to
many more functional proteins than we have genes. There are 21 000 genes but because of
things like glycosylation, phosphorylation a protein can have several functions.
When the DNA is transcribed, pre-mRNA is formed. It can only leave the nucleus when it is
matured. This is done by splicing out the introns. The exons that flank each intron are fused
together in this process. All processed and unprocessed RNA together in the nucleus is
called the hnRNA (heterogenous nucleus RNA). The pre-mRNA can also be processed
through alternative splicing in which there is a different combination of exons. These can
then carry altered reading frames. The splicing can also affect untranslated regions that can
interact with miRNAs which can then also alter the function of the mRNA. There are proteins
that are responsible for alternative splicing and when these are expressed in high levels, a
cell can become cancerous (transformation of the cell).
1.7 Gene expression patterns also control the phenotype.
The process in which cells get a distinct phenotype is called differentiation. In the end, they
will become committed to a cell type. All genes can be divided into two large groups;
housekeeping and tissue-specific.
1.8 Histone modification and transcription factors control
gene expression
The sequence motif is the specific stretch of nucleotide sequence to which the transcription
factors bind. This is usually 5-10 nucleotides. Some transcription factors can provide and
RNA polymerase (II) whereas others can block. A single TF can elicit multiple changes which
is called pleiotropy. Transcription of most genes is dependent on several distinct TFs thar
must sit at each
, own appropriate position (enhancer) in or near the promotor. All together it is called the
expression program.
This figure suggests that there is transcription in one direction downstream of the promotor,
but for many genes it can be in both directions. There can be transcriptional pausing after
reading 60-80 nucleotides and then an another stalled polymerase complex is initiated. In
addition, there is not only interaction with DNA, but also with the chromatin. The chromatin is
formed by DNA bound to nucleosomes. The nucleosomes consists of two copies of four
distinct histone species (H2A, H2B, H3 and H4) and a fifth one H1.
The chromatin structure can then be affected by post-translational modification of the
standard four histones. The N-terminals can be methylated, phosphorylated, acetylated and
ubiquitylated. Phosphorylation is associated
with condensation (during mitosis and
global shutdown of gene expression).
Acetylation is generally associated with
active gene expression. The state of the
chromatin can be passed from mother to
daughter cells. These modifications are
added by histone writers and removed by
histone erasers. Trimethylation of H3 at K4
results in gene activation. Trimethylation at
K9 and K27 results in gene repression. For
each position there is a specific writer and eraser.
1.9 Heritable gene expression is controlled through
additional mechanisms
This is via epigenetics. In addition to the histone modification there is also covalent
modification of the DNA itself via DNA methyltransferases. These can attach methyl groups
to the cytosine bases of CpG dinucleotides. C is then at 5' and G at 3'. The affected CpG is
often near transcriptional promotors and therefore it leads to gene repression. The
methylation is maintained by recognition of hemi-methylated segments by maintenance DNA
methyltransferase. Still, the mechanisms of de novo methylation is poorly understood. CpG
methylation cannot on its own block transcription, but they affect the structure of chromatin
proteins.
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