Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1134 Chapter 20: Cancer
NORMAL CELL HAS TWO ALTERNATIVE
DNA REPAIR PATHWAYS
DRUG BLOCKS
PATHWAY 1
DNA replication
occasional
accident
1 2 1
DNA replication
continues, due to
repair by pathway 2
CELL LIVES
repair by pathway
2 still possible
TUMOR CELL HAS LOST DNA
REPAIR PATHWAY 2
DRUG BLOCKS
PATHWAY 1
DNA replication
DNA replication
permanently
blocked
CELL DIES
occasional
accident
repair by pathway
2 not possible
Figure 20–41 How a tumor’s genetic
instability can be exploited for cancer
therapy. As explained in Chapter 5, the
maintenance of DNA sequences is so
critical for life that cells have evolved
multiple pathways for repairing DNA
damage and reducing DNA replication
errors. As illustrated, a DNA replication
fork will stall whenever it encounters a
break in a DNA template strand. In this
example, normal cells have two different
repair pathways that help them to avoid
the problem, pathways 1 and 2. They are
therefore not harmed by treatment with a
drug that blocks repair pathway 1. But,
because the inactivation of repair pathway
2 was selected for during the evolution of
the tumor cell, the tumor cells are killed by
the same drug treatment.
In the actual case that underlies this
example, the function of repair pathway 1
(requiring the PARP protein discussed in
the text) is to remove persistent, accidental
breaks in a DNA single strand before they
are encountered by a moving replication
fork. Pathway 2 is the recombinationdependent
process (requiring the Brca2
and Brca1 proteins) for repairing stalled
replication forks illustrated in Figure 5–50.
PARP inhibitors have promise for treating
cancers with defective Brca2 or Brca1
tumor suppressor genes.
MBoC6 m20.50/20.41
suppressor genes. As described in Chapter 5, Brca2 is an accessory protein that
interacts with the Rad51 protein (the RecA analog in humans) in the repair of
DNA double-strand breaks by homologous recombination. Brca1 is another
protein that is also required for this repair process. Like Rb, the Brca1 and Brca2
genes were discovered as mutations that predispose humans to cancer—in this
case, chiefly cancers of the breast and ovaries (though unlike Rb, they seem to be
involved in only a small proportion of such cancers). Individuals who inherit one
mutant copy of Brca1 or Brca2 develop tumors that have inactivated the second
copy of the same gene, presumably because this change makes the cells genetically
unstable and speeds tumor progression.
While Brca1 and Brca2 are needed for the repair of DNA double-strand breaks,
single-strand breaks are repaired by other machinery, involving an enzyme called
PARP (polyADP-ribose polymerase). This understanding of the basic mechanisms
of DNA repair led to a striking discovery: drugs that block PARP activity kill
Brca-deficient cells with extraordinary selectivity. At the same time, PARP inhibition
has very little effect on normal cells; in fact, mice that have been engineered
to lack PARP1—the major PARP family member involved in DNA repair—remain
healthy under laboratory conditions. This result suggests that, while the repair
pathway requiring PARP provides a first line of defense against persistent breaks in
a DNA strand, these breaks can be repaired efficiently by a genetic recombination
pathway in normal cells. In contrast, tumor cells that have acquired their genetic
instability by the loss of Brca1 or Brca2 have lost this second line of defense, and
they are therefore uniquely sensitive to PARP inhibitors (Figure 20–41).
PARP inhibitors are still under clinical trial, but they have produced some striking
results, causing tumors to regress in many Brca-deficient patients and delaying
progression of their disease, with relatively few disagreeable side effects. These
drugs also appear to be applicable to cancers with other mutations that cause
defects in the cell’s homologous recombination machinery—a small, though significant,
proportion of cancer cases.