ATR kinases

OVCAR-3 cells S phase arrest, (phosphorylation of Cdc25c at tyrosine 15 residue,(phosphorylation of H2A.Xat serine 139 residue, (chkl/2 expression, (ATM/ ATR kinase activity Tyagi et al., 2005... 

Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 2001 15(17) 2177-2196. 

Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, et al. 1999. Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res. 59 4375-82... 

Moreover, the CSN is involved in checkpoint control. The double deletions of csnl and csn2 mutants crossed with checkpoint pathway mutants such as rad3, chk, and cdsl are synthetically lethal in S. pombe [52]. Cdsl kinase is constitutively activated in csnl mutants. Similarly, loss of csn5 in Drosophila results in activation of Mei-41, one of the ATM/ATR family kinases involved in meiotic checkpoint upon DNA damage [90]. 

The invariant SQ motif in the C-terminus of H2AX is a consensus sequence for the 3 kinases belonging to the PIKK family, namely ATM, DNA-PK and ATR (Stiff et al, 2004). These kinases are involved in DNA repair. ATM [ataxia telangiectasia (A-T) mutated protein] is a crucial kinase for the signal transduction DSB pathway (Savitsky et al, 1995) and it is widely accepted that ATM is the major kinase involved in the in vivo phosphorylation of H2AX (Burma et al, 2001 Fernandez-Capetillo et al, 2002 Redon et al, 2002). The two other kinases were also associated with the generation y-H2AX, but they appeared not to be dominant (Redon et al, 2002 Stiff et al, 2004). 

SI39 (for mammals). The responsible kinases are members from phosphatidyli-nositol 3-kinase (PI3K)-like family kinases, which include ataxia telangiectasia mutated (ATM), AT-related (ATR), and DNA dependent protein kinase (DNA-PK) (Burma et al, 2001 Stiff et al, 2004 van Attikum and Gasser, 2005). Histone H2AX phosphorylation is directly related to repair of damaged chromatin (for details see chapter on Role of histone phosphorylation in chromatin dynamics and its implication in diseases ). 

Members of the phosphoinositide (PI)-3 kinase family appear to be involved in the phosphorylation of H2A.X. The SQ motif matches a common target site for these kinases and the formation of y-H2A.X in response to double stranded breaks is inhibited by wortmannin, an inhibitor of PI-3 kinases [63]. Examination of cell lines deficient in the PI-3 kinase ATM indicated that it has a major role in phosphorylating H2A.X in response to double strand breaks [64]. ATM can phosphorylate H2A.X in vitro suggesting that it may directly phosphorylate H2A.X in vivo [64]. Another PI-3 kinase ATR appears to be involved in phosphorylating H2A.X in response to replicational stress induced by treatment of dividing cells with hydroxyurea or by irradiating them with ultraviolet light [65]. It has been hypothesized that PI-3 kinases such as ATM are recruited to, or activated at, the site of the double stranded break and then phosphorylate H2A.X molecules around the break point [40,64,66]. 

Phosphorylation of H2AX appears to be the product of three regulated signaling pathways involving the kinases DNA-PK, ATM (Ataxia Telengiectasia Mutated), and ATR (AT-Rad3 related). These enzymes display both redundancy and... 

When the protein kinases ATM and ATR detect damage to DNA, such as a single-strand break, they activate p53 to serve as a transcription factor that stimulates the synthesis of the protein p21 (Fig. 12-46). This protein inhibits the protein kinase activity of cyclin E-CDK2. In the presence of p21, pRb remains unphosphorylated and bound to E2F, blocking the activity of this transcription factor, and the cell cycle is arrested in Gl. This gives the cell time to repair its DNA before entering the S... 

Figure 19.12 Regulation of liver acetyl-CoA carboxylase and cholesterol biosynthesis by phosphorylation. ACC indicates acetyl-CoA carboxylase. Bold arrow indicates activation of kinase kinase by fatty acyl-CoA. (Reproduced by permission from Hardie DG, Carling D, Sim ATR. The AMP-activated protein kinase a multi-substrate regulator of lipid metabolism. Trends Biochem Sci 14 20-23, 1989.)...

Hardie DG, Carling D, Sim ATR. The AMP-activated protein kinase a multisubstrate regulator of lipid metabolism. Trends Biochem Sci January 20, 1989. 

Jazayeri A, Ealck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat. Cell. Biol. 2006 8 37 5. Kaneko YS, Watanabe N, Morisaki H, Akita H, Fujimoto A, Tominaga K, Terasawa M, Tachibana A, Ikeda K, Nakanishi M. Cell-cycle-dependent and ATM-independent expression of human Chkl kinase. Oncogene 1999 18 3673-3681. 

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