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Summary SSA12 Maintenance of genomic integrity
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Summary and WG answers for SSA12 Maintenance of genomic integrity of the course MBO (molecular biology and oncology) at University of Leiden
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SSA12 Maintenance of genomicintegrity
Chapter 12 Weinberg
The fact that tumorigenesis is a multi-step process reflects the multiple lines of defense
against cancer. Stability of the DNA is the most robust one. Cancer cells have to have so
many mutational events in the same cell, that when the repair mechanisms are all
functioning, this would not be possible. Their genomes is more mutable; mutator phenotype.
12.1 Tissues are organized to minimize the progressive
accumulation of mutations
The stem cell compartment is only 0.1-1% of cells in a tissue. They represent the stable
repository of genetic information in a tissue and therefore the genomes must be protected.
The exponential increase in the number of transit-amplifying cells means that a stem cell only
needs to divide sometimes. The transit amplifying cells thus replicate the most and this
protects the stem cells from undergoing many divisions in which errors could occur during
the replication.
Epithelial cells are the most vulnerable. The differentiated end-stage cells have a finite
lifetime and will eventually die. Transit-amplifying cells then need to replenish these. They
have to undergo many mitotic divisions and therefore they are at increased risk of sustaining
mutations. However, because their post-mitotic variants will die, there is low risk for
tumorigenesis.
The stem cells of the enterocytes are in the depth of the crypts. There is mucus here which
prevents possible toxic/carcinogenic agents from coming in contact with these cells. APC
plays an important role to keep these cells here.
In theory the stem cell compartment is inexhaustible due to their self-renewing abilities.
However, sometimes a stem cell will die and this one needs to be replenished by symmetric
division of another stem cell. Symmetric division increases the stem cell compartment size.
Asymmetric divisions maintain the tissue size.
12.2 Stem cells may or may not be targets of the
mutagenesis that leads to cancer
Differentiated cells are unlikely to cause cancer as they are so rapidly discarded, so rapidly
that there is not enough time for enough mutations to occur. However, with an experiment
with 5-FU which kills cells with an active cell cycle, there was no reduction in the occurrence
of tumors when they were exposed to an initiator and a promotor. This shows that the cancer
causing cell is not dividing a lot.
In many hematopoietic cancers the Philadelphia chromosome (bcr-abl fusion) is found. This
indicates that this translocation occurs in a common progenitor of the cells; a pluripotent
stem cell. There are other indications as blocking of differentiation is a frequent theme in the
development of hematopoietic malignancies.
Progenitor cells can also be a target as they can get mutations that cause de-differentiation.
These transit-amplifying cells are also a logical target as their number is way higher and they
are actively dividing unlike stem cells. It could also be that carcinogens that are cytotoxic
, cause a lot of cell loss (also of stem cells) and that the stem cells then need to be
replenished through de-differentiation of the transit-amplifying cells. Complete carcinogens
work both as an initiator and a promotor.
12.3 Apoptosis, drug pump, and DNA replication mechanisms
offer tissues a way to minimize the accumulation of mutant
stem cells
Two ways to protect the stem cells already are: (1) Relative infrequent replication and (2)
anatomical protective sites. Another important thing is the DNA repair mechanism. Cancer
stem cells have more resistance to apoptosis and enhanced DNA repair mechanisms which
makes them more resistant to radiation and chemotherapy. The stem cells also actively
pump out stuff as was discovered with experiments in which they used fluorescent dyes. This
is due to expression of Mdr1 so they can actively pump out cancer drugs.
Another important mechanism to keep the genome as intact as possible in stem cells is that
the unreplicated parental DNA strand is allocated to the daughter that remains a stem cell.
Therefore, it cannot get mutations due to replication errors.
12.4 Cell genomes are threatened by errors made during
DNA replication
Common ways to get genomic alterations:
1. Errors of DNA polymerase during the S phase
2. Spontaneous chemical changes in the nucleotides
3. Attack by mutagenic agents
The basic replication machinery is aided by three other DNA polymerases: pol-α, pol-δ, and
pol-ε. The cell has two major strategies for detecting and removing errors. One is during the
DNA replication; while the polymerase is lengthening the DNA in 5' to 3' direction, there is 3'
to 5' proofreading. The polymerase also has 3' to 5' exonuclease activity so that it can move
backwards to remove a wrong nucleotide. It can then use the existing 3'-OH as a primer to
continue. Pol-δ is vital for this.
Another mechanism is the mismatch repair (MMR). The
enzymes of this monitor the recently synthesized DNA for
miscopied DNA sequences. This mechanism is especially
important for regions that have
repeating sequences in which
strand slippage can occur (due
to stutter of pol- δ). It can result
in deletions or insertions.
Highly repeated sequences
have been called satellite
sequences and there are many
microsatellites in the genome.
Defective MMR system leads
to microsatellite instability.
Besides this, MMR is also
important to remove base
substitutions. MMR-defective
cells have many mutations in
the genome. Mismatched
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