ATM/ATR regulation of G1/S and S/G2
checkpoints
DNA damage checkpoints are biochemical pathways that delay or arrest the cell cycle
progression in response to the DNA damage. All eukaryotic cells have four phases within
the cell cycle, G1, S, G2, and M, and one outside, G0 [1].
The G1/S checkpoint prevents cells from entering the S phase in the presence of the
DNA damage by inhibiting the initiation of replication. There are two signal transduction
pathways, one to initiate and one to maintain the G1/S arrest [1].
If the DNA damages are double-strand breaks (DSB) caused by ionizing radiation or
radiomimetic agents, ataxia telangiectasia mutated serine-protein kinase
(ATM) is activated [2].
The reaction that initiates the G1/S arrest is phosphorylation of cell cycle
checkpoint kinase 2
(Chk2) [1] or cell cycle checkpoint kinase 1
(Chk1) [3]
by ATM. Nuclear factor with BRCT domians protein 1
(NFBD1) may participates in transfer signal from
ATM to Chk2 [4]
and other regulators (e.g. tumor suppressor
p53 [5], [6]
and breast and ovarian cancer susceptibility protein 1
(Brca1) [7].
Phosphorylated Chk2 in turn inactivates by
phosphorylation cell division cycle 25A phosphatase
(Cdc25A). Lack of active
Cdc25A results in the accumulation of the phosphorylated
(inactive) form of Cdk2, which is incapable to participate
in initiation of replication [1].
14-3-3 proteins participate in regulation activity of some elements G1/S checkpoint
pathway (e.g. Chk1 [8],
Cdc25A [9] and p53
[10], [11] by controlling the nuclear and cytoplasmic
distribution it.
In addition, ATM may regulate oxidative stress-induced
signaling cascades involving nuclear factor-kappaB (NF-KB),
a transcription factor that is upstream of a wide variety of stress-responsive genes. For
example, NF-KB activates the transcription
of c-Myc [12] (which in turn
activates transcription of Cdc25A [13] and tumor
suppressor p53 [14].
If the DNA damage is caused by UV light or UV-mimetic
agents, the signal leads to phosphorylation of serine/threonine-protein kinase
Chk1 by ataxia telangiectasia and Rad3 related
protein kinase
(ATR) with a
participation cell cycle checkpoint control rell cycle regulator
RAD9 and claspin. The activated
Chk1 then phosphorylates
Cdc25A, leading to G1 arrest. 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 [15].
Then this rapid response via
Chk-Cdc25A pathways is followed
by the p53-mediated maintenance of G1/S arrest. In the
maintenance stage, ATM or ATR
phosphorylates Ser15 of p53 directly and Ser20 through
activation of Chk2 or Chk1
[1]. In addition, the essential elements of p53
regulation are ubiquitination [16] and sumoylation [17].
Phosphorylated p53 activates its target genes, including
cyclin-dependent kinase inhibitor 1A (p21), which binds to
cyclin-dependent kinase 2 (Cdk2)
and cyclin-dependent kinase 4
(Cdk4). It inhibits binding between Cdk
and cyclins [1]. Moreover, the
DNA damage activates p53 via inhibition its repressor - the
ubiquitin-protein ligase E3 MDM2 [18].
The intra-S-phase checkpoint is activated by damage encountered during the S phase or
by unrepaired damage that escapes the S/G2 checkpoint and leads to a block in
replication. In this pathway ATM phosphorylation of
structural maintenance of chromosomes 1-like 1 protein
(SMC1) and Fanconi anemia complementation group D2 protein,
isoform 1 (FANCD2), with the help of Nibrin,
leads to inhibition of replication. It supposed, that phosphorylation
of SMC1 results to the repression sister chromatid cohesion
[19]. FANCD2 may participate in inhibition of
replication via activation Brca1. Brca1
is phosphorylated by
ATR (perhaps, with the aid of
BML) or ATM, and activates
transcription of growth arrest and DNA-damage-inducible transcripts alpha and beta
(GADD45 alpha/beta). In addition, the transcription of
GADD45 alpha/beta may be regulated by
p53. GADD45 alpha/beta was
found to bind to proliferating cell nuclear antigen (PCNA),
a protein involved in DNA replication and repair. p21 blocks
the ability of PCNA to bind with Gadd45
[20].
In addition, Chk2 / Cdc25A
pathway participates in the S/G2 checkpoint arrest too [21].
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