ATM/ATR regulation of G2/M checkpoint
DNA damage checkpoints are biochemical pathways that delay or arrest cell cycle
progression in response to DNA damage. All eukaryotic cells have four phases within the
cell cycle, G1, S, G2, and M, and one outside, G0. The G2/M checkpoint prevents cells
from undergoing mitosis in the presence of DNA damage .
If the DNA damage predominantly consists of double-strand breaks (DSB) caused by
ionizing radiation or radiomimetic agents, ataxia telangiectasia mutated serine-protein
kinase (ATM) gets activated
. So-called MRN
complex plays an essential role in stimulation of
Phosphorylation of cell cycle checkpoint kinase 2
(Chk2).or cell cycle checkpoint kinase 1
(Chk1) by ATM initiates G2/M
arrest , . Nuclear factor with BRCT domain protein 1
(NFBD1) may participates in transfer signal from
ATM to Chk2 
and other regulators (e.g. tumor suppressor
p53 , 
and breast and ovarian cancer susceptibility protein 1
If the DNA damage is caused by UV light or UV-mimetic
agents, the signal leads to phosphorylation of kinase Chk1
by ataxia telangiectasia and Rad3 related protein
participation of the cell cycle checkpoint control protein
RAD9 and claspin. It is shown,
that ATR phosphorylates ATR interacting
protein (ATRIP), which, in
turn, regulates ATR expression, and is an essential
component of the DNA damage checkpoint pathway . Chk1 may be activated via
breast and ovarian cancer susceptibility protein 1
(Brca1) pathway . 14-3-3 proteins may
participate in regulation of activation of Chk1, as well
Activated Chk 1, in turn, inactivates by phosphorylation
the group of cell division cycle 25A phosphatases
(Cdc25s). In addition, Chk 2
inhibits Cdc25C via stimulation of Polo-like
kinase 3 (PLK3) , . 14-3-3 protein and,
mitogen-activated protein kinase 14 (p38 alpha) can inhibit
Cdc25s, as well. Lack of active
Cdc25s result in an accumulation of the phosphorylated
(inactive) form of Cyclin-dependent kinase 1
(CDK1) and mitotic arrest.
CDK1/cyclin B (or
cyclin A) complex is a key
element in cell's entry into mitosis , .
Tumor suppressor p53 plays the key role in the G2/M
checkpoint arrest . ATM or
ATR phosphorylate Ser15 of p53
directly and Ser20 via activation of Chk2 or
Chk1 . In addition, Chk
2 activates p53 via PLK3
, . 53BP1
probaly takes a part in this
process . Essentially, p53
regulation is accompanied by ubiquitination  and
sumoylation . p53 regulates translation
of some proteins (e.g. growth
arrest and DNA-damage-inducible transcripts alpha and beta (GADD45
alpha/beta) , Cyclin-dependent kinase inhibitor 1A
(p21), CDK1 and
cyclin B ).
p21 , GADD45 alpha/beta
 and 14-3-3 proteins  inhibit CDK1. In
addition, during G2, the CDK1/Cyclin
B complex is kept inactive by phosphorylation on tyrosine 15 and threonine
14 of CDK1 by the kinases Wee1
 and Myt1 , respectively.
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DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
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Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints.
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NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage.
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NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors.
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ATR and ATRIP: partners in checkpoint signaling.
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BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage.
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Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345.
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Regulation of the G2/M transition by p53.
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Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway.
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UV induces GADD45 in a p53-dependent and -independent manner in human keratinocytes.
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p21 inhibits Thr161 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint.
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The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression.
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Wild-type TP53 inhibits G(2)-phase checkpoint abrogation and radiosensitization induced by PD0166285, a WEE1 kinase inhibitor.
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The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex.
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