CANCER GENOME STABILITY
Repair Enzymes
Mammalian cells have a backup strategy for minimizing the genetic damage caused by these potential
carcinogens.
The simplest strategy for restoring the structure of
chemically altered DNA involves an enzyme-catalysed
reversal of the chemical reaction that initially crated the
altered base. For example, one type of DNA
alkyltransferase removes methyl and ethyl adducts from
the O6 position of guanine, thereby restoring the structure
of the normal base.
Repair enzymes can also influence the types of tumors
caused by certain carcinogens in animal models of cancer,
and quite possibly in humans.
Bacterial AlkB
- The MGMT system is only one way which cells deal with methylated bases. Another involving
homologs of bacterial AlkB DNA repair protein, works by oxidizing methyl groups that have become
attached to bases, which are then shed as formaldehyde from the rings of all four DNA bases;
similarly, AlkB enzymes cause the larger ethyl group to be released as acetaldehyde.
- Bacterial AlkB has also been found to be capable of removing more complex adducts. For example,
the inadvertent oxidation of unsaturated lipids, yielding lipid epoxides and peroxides, occurs at high
rates in inflamed tissues; these highly reactive chemical groups can generate complex adducts with
DNA bases that are highly mutagenic.
BASE-EXCISION REPAIR AND NUCLEOTIDE-EXCISION REPAIR
In some cases, specialized enzymes will cleave the bond linking a modified base to the deoxyribose
sugar, the process of base-excision repair.
In other cases, the entire nucleotide containing both base and associated deoxyribose will be cut out,
this being the process termed nucleotide-excision repair.
Base-Excision Repair:
Base-excision repair tends to repair lesion in the DNA
that derive from endogenous sources, such as those
attributed to the reactive oxygen species and
depurination events described earlier.
Nucleotide-excision repair, in contrast, largely repairs
lesions created by exogenous agents, such as UV
photons and chemical carcinogens. Directs its attention
to bulky, helix-distorting alterations.
Base-excision repair is initiated by a group of DNA
glycosylases, each specialized to recognize an abnormal
base and cleave its covalent bond to deoxyribose.
Any mutant sequences that result from this bypass
synthesis may subsequently be repaired by consulting the
wild-type sequences present in the “sister chromatid”, that
is, the other newly synthesized double helix formed by
the replication fork.
This process is termed error-prone DNA replication, since
, Nucleotide-Excision Repair:
Nucleotide-excision repair is accomplished by a large multiprotein complex composed of almost two
dozen subunits. This complex seems to require two distinct changes in DNA before it will initiate
repair: significant distortion of the normal structure of the double helix plus the presence of a
chemically altered base. Once this large complex recognizes the problem, it proceeds to cleave the
damaged strand upstream and downstream of the damage, yielding a single-strand fragment of 25-3-
nucleotides in length, which is then removed.
DNA polymerases that are specialized to fill in the resulting gap in the DNA then take over, followed
by a DNA ligase, which erases the final trace of the damage.
The various reactions that constitute nucleotide-excision repair can actually be divided into two
subtypes:
- The first of these is focused specifically on the template strand of actively transcribed genes
and is coupled to the actions of RNA polymerase molecules that are proceeding down these
template strands during transcription; these actions are termed transcription-coupled repair.
- The second subtype of nuclear-excision repair addresses that remainder of the genome,
including the nontemplate strand of transcribed genes as well as the nontranscribed regions of
the genome. This type of nuclear-excision repair is sometimes termed global genomic repair.
The overexpression of the error-prone DNA polymerase β may represent an effective strategy used by
these cancer cells to increase the mutability of their genes and gene accelerate the rate of tumor
progression.
The bypass polymerases are not DNA repair enzymes, since they are not focused primarily on removing
damage and restoring wild-type nucleotide sequences.
AID Enzyme
AID enzyme is encoded by the mammalian genome that purposely inserts mutation into the genome.
It may also contribute to cancer development.
By converting cytidine to uridine residues, this enzyme effectively inserts numerous C-to-T point
mutations in these genes; in the case of immunoglobulin (antibody) genes, the resulting “somatic
hypermutation” causes diversification of the antigen-binding sites of the encoded antibody molecules,
enabling the immune system to develop antibodies of ever-increasing avidity for their antigen ligands.
Heritable Defects in DNA Repair That Leads to Cancer
On many occasions, the hybrids were found to repair DNA normally, indicating that the two parental
cells carried defects in DNA repair that were associated with two distinct genes.
Genetic complementation led to the classification of XP-associated mutant alleles into eight
complementation groups, each ostensibly defined by the identity of a responsible gene.
Seven of the eight XP-associated genes, named XPA through XPG,
encode components of the large, multiprotein nucleotide-excision repair
complex.
High rates of mutations in genes that have microsatellite repeats nested
in their sequences.
The MMR defect and resulting mutant alleles were discovered in
sporadic (rather than familial) cancers. These observations point to the
fact that in nonfamilial tumors, MMR genes like tumor suppressor
genes, can be rendered defective either by somatic mutation or by
promoter methylation and resulting transcriptional silencing.
Cells that have lost MLH1 or MSH2 expression also do not recognize
the damage inflicted by alkylating mutagens that would normally
activate G2/M cell cycle checkpoint or induce apoptosis; such cells
Repair Enzymes
Mammalian cells have a backup strategy for minimizing the genetic damage caused by these potential
carcinogens.
The simplest strategy for restoring the structure of
chemically altered DNA involves an enzyme-catalysed
reversal of the chemical reaction that initially crated the
altered base. For example, one type of DNA
alkyltransferase removes methyl and ethyl adducts from
the O6 position of guanine, thereby restoring the structure
of the normal base.
Repair enzymes can also influence the types of tumors
caused by certain carcinogens in animal models of cancer,
and quite possibly in humans.
Bacterial AlkB
- The MGMT system is only one way which cells deal with methylated bases. Another involving
homologs of bacterial AlkB DNA repair protein, works by oxidizing methyl groups that have become
attached to bases, which are then shed as formaldehyde from the rings of all four DNA bases;
similarly, AlkB enzymes cause the larger ethyl group to be released as acetaldehyde.
- Bacterial AlkB has also been found to be capable of removing more complex adducts. For example,
the inadvertent oxidation of unsaturated lipids, yielding lipid epoxides and peroxides, occurs at high
rates in inflamed tissues; these highly reactive chemical groups can generate complex adducts with
DNA bases that are highly mutagenic.
BASE-EXCISION REPAIR AND NUCLEOTIDE-EXCISION REPAIR
In some cases, specialized enzymes will cleave the bond linking a modified base to the deoxyribose
sugar, the process of base-excision repair.
In other cases, the entire nucleotide containing both base and associated deoxyribose will be cut out,
this being the process termed nucleotide-excision repair.
Base-Excision Repair:
Base-excision repair tends to repair lesion in the DNA
that derive from endogenous sources, such as those
attributed to the reactive oxygen species and
depurination events described earlier.
Nucleotide-excision repair, in contrast, largely repairs
lesions created by exogenous agents, such as UV
photons and chemical carcinogens. Directs its attention
to bulky, helix-distorting alterations.
Base-excision repair is initiated by a group of DNA
glycosylases, each specialized to recognize an abnormal
base and cleave its covalent bond to deoxyribose.
Any mutant sequences that result from this bypass
synthesis may subsequently be repaired by consulting the
wild-type sequences present in the “sister chromatid”, that
is, the other newly synthesized double helix formed by
the replication fork.
This process is termed error-prone DNA replication, since
, Nucleotide-Excision Repair:
Nucleotide-excision repair is accomplished by a large multiprotein complex composed of almost two
dozen subunits. This complex seems to require two distinct changes in DNA before it will initiate
repair: significant distortion of the normal structure of the double helix plus the presence of a
chemically altered base. Once this large complex recognizes the problem, it proceeds to cleave the
damaged strand upstream and downstream of the damage, yielding a single-strand fragment of 25-3-
nucleotides in length, which is then removed.
DNA polymerases that are specialized to fill in the resulting gap in the DNA then take over, followed
by a DNA ligase, which erases the final trace of the damage.
The various reactions that constitute nucleotide-excision repair can actually be divided into two
subtypes:
- The first of these is focused specifically on the template strand of actively transcribed genes
and is coupled to the actions of RNA polymerase molecules that are proceeding down these
template strands during transcription; these actions are termed transcription-coupled repair.
- The second subtype of nuclear-excision repair addresses that remainder of the genome,
including the nontemplate strand of transcribed genes as well as the nontranscribed regions of
the genome. This type of nuclear-excision repair is sometimes termed global genomic repair.
The overexpression of the error-prone DNA polymerase β may represent an effective strategy used by
these cancer cells to increase the mutability of their genes and gene accelerate the rate of tumor
progression.
The bypass polymerases are not DNA repair enzymes, since they are not focused primarily on removing
damage and restoring wild-type nucleotide sequences.
AID Enzyme
AID enzyme is encoded by the mammalian genome that purposely inserts mutation into the genome.
It may also contribute to cancer development.
By converting cytidine to uridine residues, this enzyme effectively inserts numerous C-to-T point
mutations in these genes; in the case of immunoglobulin (antibody) genes, the resulting “somatic
hypermutation” causes diversification of the antigen-binding sites of the encoded antibody molecules,
enabling the immune system to develop antibodies of ever-increasing avidity for their antigen ligands.
Heritable Defects in DNA Repair That Leads to Cancer
On many occasions, the hybrids were found to repair DNA normally, indicating that the two parental
cells carried defects in DNA repair that were associated with two distinct genes.
Genetic complementation led to the classification of XP-associated mutant alleles into eight
complementation groups, each ostensibly defined by the identity of a responsible gene.
Seven of the eight XP-associated genes, named XPA through XPG,
encode components of the large, multiprotein nucleotide-excision repair
complex.
High rates of mutations in genes that have microsatellite repeats nested
in their sequences.
The MMR defect and resulting mutant alleles were discovered in
sporadic (rather than familial) cancers. These observations point to the
fact that in nonfamilial tumors, MMR genes like tumor suppressor
genes, can be rendered defective either by somatic mutation or by
promoter methylation and resulting transcriptional silencing.
Cells that have lost MLH1 or MSH2 expression also do not recognize
the damage inflicted by alkylating mutagens that would normally
activate G2/M cell cycle checkpoint or induce apoptosis; such cells
