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Pharmacological effect
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Organism specific object

DNA damage ATM/ATR regulation of G1/S checkpoint


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DNA damage ATM/ATR regulation of G1/S checkpoint

ATM/ATR regulation of G1/S and S/G2 checkpoints

DNA damage checkpoints are biochemical pathways that delay or arrest the cell cycleprogression in response to the DNA damage. All eukaryotic cells have four phases withinthe 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 theDNA damage by inhibiting the initiation of replication. There are two signal transductionpathways, 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 orradiomimetic agents, ataxia telangiectasia mutated serine-protein kinase ( ATM )is activated [2].

The reaction that initiates the G1/S arrest is phosphorylation of c ell cyclecheckpoint kinase 2 ( Chk2 ) [1] or c ell 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 cycle25A phosphatase ( Cdc25A ). Lack of active Cdc25A results in theaccumulation of the phosphorylated (inactive) form of Cdk2, which is incapable toparticipate in initiation of replication [1].

14-3-3 proteins participate in regulation activity of some elements G1/S checkpointpathway (e.g. Chk1 [8], Cdc25A [9] and p53[10], [11] by controlling the nuclear and cytoplasmicdistribution it.

In addition, ATM may regulate oxidative stress-induced signaling cascadesinvolving nuclear factor-kappaB ( NF-KB ), a transcription factor that is upstreamof a wide variety of stress-responsive genes. For example, NF-KB activates thetranscription of c-Myc [12] (which in turn activates transcription ofCdc25A [13] and tumor suppressor p53 [14].

If the DNA damage is caused by UV light or UV-mimetic agents, the signal leadsto phosphorylation of serine/threonine-protein kinase Chk1 by ataxiatelangiectasia and Rad3 related protein kinase ( ATR ) with a participation cellcycle checkpoint control rell cycle regulator RAD9 and claspin. Theactivated Chk1 then phosphorylates Cdc25A, leading to G1 arrest. It isshown, that ATR phosphorylates ATR interacting protein ( ATRIP ), which inturn regulates ATR expression, and is an essential component of the DNAdamage checkpoint pathway [15].

Then this rapid response via Chk - Cdc25A pathways is followed by thep53 -mediated maintenance of G1/S arrest. In the maintenance stage, ATM orATR phosphorylates Ser15 of p53 directly and Ser20 through activation ofChk2 or Chk1 [1]. In addition, the essential elements ofp53 regulation are ubiquitination [16] and sumoylation [17].

Phosphorylated p53 activates its target genes, including cyclin-dependentkinase inhibitor 1A ( p21 ), which binds to cyclin-dependent kinase 2 (Cdk2 ) and cyclin-dependent kinase 4 ( Cdk4 ). It inhibits binding betweenCdk and cyclins [1]. Moreover, the DNA damage activatesp53 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 orby unrepaired damage that escapes the S/G2 checkpoint and leads to a block inreplication. In this pathway ATM phosphorylation of structural maintenance ofchromosomes 1-like 1 protein ( SMC1 ) and Fanconi anemia complementation group D2protein, isoform 1 ( FANCD2 ), with the help of Nibrin, leads to inhibitionof replication. It supposed, that phosphorylation of SMC1 results to therepression sister chromatid cohesion [19]. FANCD2 may participate ininhibition of replication via activation Brca1. Brca1 is phosphorylated byATR (perhaps, with the aid of BML ) or ATM, and activatestranscription of growth arrest and DNA-damage-inducible transcripts alpha and beta (GADD45 alpha/beta ). In addition, the transcription of GADD45 alpha/betamay be regulated by p53. GADD45 alpha/beta was found to bind toproliferating cell nuclear antigen ( PCNA ), a protein involved in DNA replicationand repair. p21 blocks the ability of PCNA to bind with Gadd45[20].

In addition, Chk2/ Cdc25A pathway participates in the S/G2 checkpointarrest too [21].