Biology Reference
In-Depth Information
When made
(before, during,
after replication)
Potential
biomarkers*
Inhibitors in
development
Pathway
Repairs made
Comments
DR
Removes alkyl groups by
direct transfer
Before
MGMT
MGMT
Very fast but saturable reaction
Gene therapy to overexpress MGMT may provide myeloprotection, if
clinical trials are successful
BER
Non-bulky lesions produced
by alkylation, oxidation or
deamination of bases
Before
APE1
pol
b
(maybe)
XRCC1
APE1
Selective APE1 inhibitors (endonuclease vs. redox activities) are in early
clinical trials
Gene therapy to overexpress APE1 may provide myeloprotection, but
gene therapy is problematic to control
FEN1 inhibitor tested in cell studies only to date
PARP inhibitors are clinically available
A better course of action may be to inhibit lyase activity, as it is difficult to
develop a specific pol inhibitor that does not also affect replication. pol
b
inhibition can affect the MMR pathway as well, if MSH2 deficiency exists
FEN1
PARP1
pol
b
NER
Large adducts and helix-
distorting lesions to one DNA
strand, such as that induced
by cross-linking agents or
base-damaging carcinogens
During (TC-NER)
Before or after
(GG-NER)
XPA
RPA
ERCC1
ERCC2 (maybe)
XPA
RPA
XPA is not highly expressed like other NER proteins are, so XPA may be
a limiting factor in NER
MMR
Single-base mismatches and
misaligned short nucleotide
repeats, such as small
insertion/deletion loops
introduced during normal
DNA replication
During and after
MSH2
MSH3
pol
b
(maybe)
pol
g
(maybe)
MMR is historically known to act upon replication forks; the most recent
evidence shows it can act upon DNA after replication as well
MMR complexes can distinguish between template and newly replicated
DNA strands
Deficient MMR results in DNA damage tolerance and chemoresistance
HR
DSBs, when it can use a
sister chromatid for a
repair template
During S and G2
phases
PARP1
BRCA1
BRCA2
PTEN (maybe)
RAD51 (and its
foci)*
FANCD2 foci*
g
-H2AX foci*
c-Abl
PARP1
HSP90
Ubiquitine
proteasome
Imatinib (an Abl inhibitor) is clinically available
PARP inhibitors are clinically available
HSP90 inhibition prevents conformational changes and associations with
HR protein complexes
*The concept of using repair foci as biomarkers is intriguing; it would
measure functionality without needing to know all the components
involved
NHEJ
Rejoins the ends of DSBs
regard-less of sequence
homology
Before or after
Ku70
Ku80
XRCC4
DNA ligase I, IV
PNKP
Like MMR, diminished NHEJ functioning results in damage tolerance
and resistance to anticancer agents
Checkpoints
Arrest the cell cycle to
allow time for DNA
repairs
During
ATM
ATR
DNA-PKcs
ATM, ATR, DNA-
PKcs, Chk1,
Chk2, others
Unlike the inhibition of a specific DNA repair protein, checkpoint
inhibitors typically inhibit more than one kinase
Polymerases
Covalently link one
nucleotide at a time to
the end of a preexisting
DNA “primer” chain
During
TDT
Synthetic dATP
pol
b
In preclinical studies
In preclinical studies
Note:
11 non-specific nucleoside inhibitors are already in clinical use;
however, they lack the ability to selectively inhibit a specific DNA
polymerase or a class of polymerases (DNA repair vs. DNA synthesis)
In general, as the number of risk alleles increases, the chances of survival decrease.
SNPs in DSB-repair genes have clinical significance for cancer
