Biology Reference
In-Depth Information
CHAPTER
1
Introduction and Overview of DNA Repair
Target
s: From Bench to
Clinic
Mark R. Kelley
Indiana University School of Medicine, Indianapolis, IN
HISTORY OF DNA REPAIR
largely ignored in a clinical sense. By and large, the
study of DNA repair pathways languished in the realm
of academia.
However, the concept of irreparably
damaging
DNA
to kill cancer cells pharmacologically, in addition to radi-
ation, took center stage as a number of chemotherapeu-
tics moved through clinical trials into everyday use.
Although the mode of action for many anticancer agents
is to cause DNA damage, it is ironic that early develop-
ment of chemotherapeutics did not take into consider-
ation how the study of DNA repair pathways could
help determine what treatments might be most effica-
cious. Instead, the first paradigm for treating cancer
followed an infectious disease approach.
3
Akin to
matching a drug to a bug, scientists attempted to find
a specific chemotherapeutic that would eradicate a
particular type of cancer. A parallel path of concerted
research effort was expended in finding an individual
gene that would correspond to a particular type of
cancer, with the goal of either restoring lost genetic func-
tionality or silencing a tumorigenic gene function.
4
Ever since Swiss physician Friedrich Miescher iso-
lated something he called “nuclein” from cell nuclei in
1868, scientists have strived to unravel the secrets of
DNA. Knowledge of how genetic material is stored,
copied, maintained, and used gave rise to the field of
molecular biology
e
which opened new vistas for
modulating biological processes.
1
In the 1930s, genes were presumed to be (1) made of
proteins and (2) intrinsically stable, with mutations
being rare events.
2
Key discoveries such as Oswald
Avery's 1944 work with bacteria revised that thinking.
Avery showed that disease could be transferred to
a harmless strain of bacteria, then passed on to the
next generation of that strain, giving the world its first
glimpse of the fact that DNA is subject to alterations.
Other scientists' work gradually revealed the structure
of DNA, which was a key step in starting to learn how
its structure could be changed. Notably, in 1949,
biochemist Erwin Chargoff discovered that DNA
contains equal amounts of adenine and thymine (30%
each in humans) and also equal amounts of guanine
and cytosine (20% each in humans). This paved the
way for Watson and Crick's 1953 visualization of the
double helix structure of DNA.
1
By then, 20 years of studies regarding radiation's
mutagenic effects on DNA had transpired
2
TABLE 1.1 Summary of DNA Repair Pathways
DIRECT REPAIR (DR)
Base excision repair (BER)
Sub-paths:
Short-patch
Long-patch
e
but the
elaborate genome maintenance systems that control
DNA damage were yet to be elucidated. The concept
of DNA
repair
did not become a fixture in the lexicon
of molecular and cellular biology until the 1960s.
2
That
same decade, the base excision repair pathway (BER)
was discovered.
2
Although more repair pathways were
discovered over the next decade (
Table 1.1
),
2
their
importance in maintaining the integrity of the human
genome and preventing malignant transformation was
Nucleotide excision repair (NER)
Sub-paths: Global genome repair (GGR)
Transcription coupled repair (TCR)
MISMATCH REPAIR (MMR)
Non-homologous end joining (NHEJ)
Error-prone
Homologous recombination (HR)
Error-free
