Biology Reference
In-Depth Information
absence of defined DNA damage and cellular decisions
on when to induce apoptosis versus attempt repair.
Although this textbook's discussions of repair pathways
operate on the narrower definition of DNA repair, it is
worthy to mention the “damage response” side to DNA
repair, as (1) its contributions help maintain genome
integrity and (2) concerted efforts are under way to
develop checkpoint inhibitors therapeutics as well.
5,20,24
Cell replication is a highly regulated process by
necessity; this helps guarantee accurate and complete
transfer of genetic material.
25
Key contributors to this
regulation are DNA checkpoints. DNA checkpoints
function much like a quality control manager, precisely
monitoring DNA status throughout the cell cycle and
determining whether to signal it to halt when DNA
damage is sensed. DNA checkpoints allow cells to
respond to critical situations such as exposure to geno-
toxic agents or to cope with DNA lesions that cannot
be repaired immediately. In addition to controlling repli-
cation efficiency and accuracy, checkpoints may engage
in any combination of strategies if any aspect of replica-
tion goes astray. They may:
II
I
CDK 1
Cycin B
I
G0
GAP 0
M
CDK 1
Cycin A
MITOSIS
CDK 4
G2
DIVISION
Cycin D
GAP 2
II
CDK 6
G1
Cycin D
24 h
GAP 1
INTERPHASE
DNA
SYNTHESIS
S
CDK 2
CDK 2
Cycin A
Cycin E
I
FIGURE 1.4
Cell cycle phases and CDK-cyclin complexes that
drive each phase.
Reproduced by permission of John Wiley & Sons from
Wesierska-Gadek
et al.
,
Journal of Cellular Physiology
, 2011.
25
(Please
refer to color plate section).
checkpoint factors do not directly recognize the lesions;
DNA repair mechanisms do that, then they activate the
apical checkpoint kinases. If necessary, the checkpoint
signaling cascade initiates cell cycle arrest to allow
adequate time to repair DNA damage or to induce
apoptosis. Checkpoints also appear to play a role in
determining the most efficient method of DNA repair
to employ. For example, checkpoint-dependent phos-
phorylation of BRCA1 and Nej1 seems to affect whether
the HR or NHEJ pathway is used to repair DSBs.
7
Although the two proximal transducer kinases, ATM
and ATR, appear to have distinct divisions of labor
e
the former responding to DSBs, the latter responding
to stalling of replication forks during replicative
stress
e
there is overlap and coordinated cross-talk,
which is still being elucidated.
24
That is true with the
distal transducer kinases as well. Chk1 regulates both
the S and G2-M checkpoints via downstream effectors.
But Chk2 can do the same, through p53 as well as other
effectors that Chk1 influences
24
(
Figure 1.5
).
Cancers demonstrate numerous checkpoint abnormal-
ities; this dysfunction is a hallmark of tumor progression
and neoplastic transformation. For example, expression
of p53, which has signaling and regulation roles at both
cell cycle checkpoints, is decreased in many cancers.
25
In contrast, overexpression of cyclins, the regulatory
subunits of CDK-cyclin complexes, is common in
cancers.
25
In addition, chemotherapy and ionizing radia-
tion activate cell cycle checkpoints.
24
Further disruption
of these DNA damage-response systems that are already
dysfunctional in tumors could be exploited as a new
route for creating selectivity in anticancer treatments
and enhancing sensitivity to cytotoxic agents.
5,24
Prevent cell cycle progression
Segregate damaged chromosomes
Prevent generation of secondary lesions
Modify transcription
Potentiate repair actions and modulate levels of repair
proteins
Direct lesions to the most appropriate repair
pathway.
7
Thus, DNA damage checkpoints are intrinsic to cell
cycle integrity and DNA damage response.
7,24,25
Briefly, checkpoint signaling comes from five sources:
sensors, proximal and distal transducer kinases, media-
tors, and effectors. Sensors recognize structural abnor-
malities of damaged DNA or chromatin; proximal
transducer kinases function like sensors but require acti-
vation from additional proteins. Mediators assess both
the temporal and spatial progression of the DNA
damage response. When activated, both the proximal
and distal transducer kinases phosphorylate a plethora
of effector molecules involved in DNA damage response.
p53, known as the “keeper of the genome,” is the most
prominent of those. The effectors signal CDK-cyclin
complexes, which drive the consecutive phases of the
cell cycle and can halt cell cycle progression and tran-
scription. Various cyclins are expressed in different
phases of the cell cycle, and cyclin levels rise or fall
according to what phase is in progress
24,25
(
Figure 1.4
).
Checkpoints are activated at times of cell stress. If
stress in the form of DNA damage is minimal, check-
points may not be activated. Scientists are still
discerning exactly how checkpoint signaling cascades
are activated. However,
there is evidence that
the
