Biology Reference
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observed in the ATM-deficient, p53-proficient tumors could be reversed by
inhibition of another PI(3)K-like kinase involved in the DNA damage response,
DNA-PKcs. This finding could be explained by the distinct roles of ATM and
DNA-PKcs in the repair of DNA DSBs. ATM is involved in HR-mediated
error-free repair
90-95
while DNA-PKcs is an important component of the more
error-prone NHEJ-mediated repair.
96-99
The most likely explanation for the
observed synthetic lethality between ATM and DNA-PK in p53-proficient cells
was that loss of both kinases eliminated the two major pathways required for
DSB repair. In the absence of ATM, the p53-deficient cells were defective in
performing HR, and instead exhibited an increased reliance on alternative
DSB repair mechanisms, including NHEJ (
Fig. 3
).
This synthetic lethal interaction between ATM and DNA-PKcs in the
presence of chemotherapy-induced DSBs was also confirmed
in vivo
, where
suppression of DNA-PKcs was
found to resensitize ATM-depleted,
p53-proficient E
-myc-driven lymphomas to doxorubicin. Interestingly, the
inhibition of DNA-PKcs-dependent signaling had no sensitizing effect on
ATM wild-type cells or p53-deficient cells, regardless of their ATM status.
These observations are consistent with reports that the combined germline
deficiency of ATM and DNA-PKcs in mice results in early embryonic lethali-
ty.
100
These data strongly support a role for NHEJ as a backup mechanism for
DSB repair when HR is lost in p53-proficient cells, analogous to the role of HR
in the context of PARP inhibition, as discussed earlier. Whether these obser-
vations could ever be translated into clinical practice remains unclear, as small-
molecule inhibition of both ATM and DNA-PK would be expected to have very
high toxicity. DNA-PK inhibitors, however, might prove very useful in the
subset of cancer patients whose tumors have functional p53 but defective
ATM signaling as a consequence of genetic mutations or epigenetic silencing.
m
D. Synthetic Lethality Between p53 and MK2
In addition to the canonical DNA damage signaling modules ATM/Chk2
and ATR/Chk1, genotoxic stress also leads to the activation of the p38/MK2
pathway.
24-26,101-105
Activation of the p38/MK2 complex upon genotoxic stress
is dependent on both ATM and ATR
103,106
and functions in parallel and
independently of Chk1 or Chk2 activation. MK2 is a direct substrate of p38,
a MAPK that plays a central role in cellular stress responses. The p38 signaling
pathway is activated by a variety of stimuli besides DNA damage, including
cytokines, reactive oxygen species, osmotic stress, heat shock, and various
toxins.
107
Our lab found that the p38/MK2 pathway is critical for arresting the cell
cycle after ultraviolet (UV)-induced damage.
25
MK2-depleted cells were
defective in both the G1/S and G2/M checkpoints, and they became
more sensitive to DNA damage-induced cell death as a consequence of mitotic
