DNA damage - ATM / ATR regulation of G2 / M checkpoint

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 [1].

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 [2]. So-called MRN complex plays an essential role in stimulation of ATM.

Phosphorylation of cell cycle checkpoint kinase 2 (Chk2).or cell cycle checkpoint kinase 1 (Chk1) by ATM initiates G2/M arrest [1], [3]. Nuclear factor with BRCT domain 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]).

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 kinase (ATR) with 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 [8]. Chk1 may be activated via ATM/ATR - breast and ovarian cancer susceptibility protein 1 (Brca1) pathway [9]. 14-3-3 proteins may participate in regulation of activation of Chk1, as well [10].

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) [11], [12]. 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 [1], [13].

Tumor suppressor p53 plays the key role in the G2/M checkpoint arrest [14]. ATM or ATR phosphorylate Ser15 of p53 directly and Ser20 via activation of Chk2 or Chk1 [1]. In addition, Chk 2 activates p53 via PLK3 [12], [15]. 53BP1 probaly takes a part in this process [6]. Essentially, p53 regulation is accompanied by ubiquitination [16] and sumoylation [17]. p53 regulates translation of some proteins (e.g. growth arrest and DNA-damage-inducible transcripts alpha and beta (GADD45 alpha/beta) [18], Cyclin-dependent kinase inhibitor 1A (p21), CDK1 and cyclin B [14]).

p21 [19], GADD45 alpha/beta [20] and 14-3-3 proteins [14] 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 [21] and Myt1 [22], respectively.

References:

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