Biology Reference
In-Depth Information
Interestingly, curcumin, a natural spice component with both metal chela-
tion and reducing activities, was able to reverse the metal-induced inhibition of
NEILs both
in vitro
and in neuronal cells, suggesting its therapeutic
potential.
182,183
C. BER/SSBR as Cancer Therapeutic Targets:
Are We at a Crossroad?
Cellular sensitivity to DNA-damaging agents, such as ionizing radiation and
radiomimetic drugs, is generally believed to reflect their DNA repair compe-
tence. For example, high expression of APE1 in tumor tissues is linked to their
resistance to radiation and chemotherapy.
186-188
Therefore, research targeting
BER proteins, in particular APE1, for sensitizing cancer cells has been inten-
sified in recent years.
86,189-191
Among BER/SSBR proteins, PARP-1 was shown
to be an effective therapeutic target where PARP-1 inhibitors strongly en-
hanced susceptibility to radiation (IR)/chemotherapy of BRCA1-negative
human breast cancer cells, which was proposed to be due to synthetic lethal-
ity.
192,193
Resistance of tumor cells to radiation and radiomimetic drugs results
from efficient repair of induced DNA DSBs via homologous recombination
(HR), which involves BRCA1. In the absence of HR, PARP-1 inhibitors were
proposed to target SSBR, also induced by radiation and drugs.
194
However, we
propose an alternative basis for drug sensitization by PARP inhibitors. Based on
the underlying assumption that SSBs do not trigger cell death until they are
converted into DSBs via DNA replication and that DSBs activate apoptotic
signaling, we suggest that in the absence of HR, the DSBs that are produced as
replication intermediates are repaired via the alternate end joining (Alt-EJ)
pathway, which is distinct from classical nonhomologous end joining (NHEJ),
by requiring SSBR proteins including PARP-1, LigIII
a
, and XRCC1, but not
Ku, DNA-PKcs, LigIV/XRCC4, etc.
195
Unraveling the detailed molecular
mechanisms of BER/SSBR and their regulation has significant ramifications
for future cancer therapy where not only PARP1 inhibitors but also other BER/
SSBR proteins could be targeted to sensitize cancer cells, particularly when the
surviving cells develop resistance to PARP inhibitors.
VI. Conclusions and Future Perspectives
Although BER/SSBR is universally conserved, the mammalian BER/SSBR
has multiple sub-pathways, sometimes involving noncanonical proteins, com-
mensurate with the structural complexity of the genome and its organization.
Our recent studies have led us to propose a new paradigm for BER/SSBR
whose key features are as follows: (a) The DG controls the BER sub-pathway
