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

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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:

  1. Sancar A, Lindsey-Boltz LA, Unsal-Kaçmaz K, Linn S
    Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual review of biochemistry 2004;73:39-85
  2. Bakkenist CJ, Kastan MB
    DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003 Jan 30;421(6922):499-506
  3. Zhao H, Watkins JL, Piwnica-Worms H
    Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proceedings of the National Academy of Sciences of the United States of America 2002 Nov 12;99(23):14795-800
  4. Peng A, Chen PL
    NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. The Journal of biological chemistry 2003 Mar 14;278(11):8873-6
  5. Xu X, Stern DF
    NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Oct;17(13):1842-8
  6. Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP
    Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. Genes & development 2002 Mar 1;16(5):583-93
  7. Stucki M, Jackson SP
    MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes. DNA repair 2004 Aug-Sep;3(8-9):953-7
  8. Cortez D, Guntuku S, Qin J, Elledge SJ
    ATR and ATRIP: partners in checkpoint signaling. Science (New York, N.Y.) 2001 Nov 23;294(5547):1713-6
  9. Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC
    BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nature genetics 2002 Mar;30(3):285-9
  10. Jiang K, Pereira E, Maxfield M, Russell B, Goudelock DM, Sanchez Y
    Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345. The Journal of biological chemistry 2003 Jul 4;278(27):25207-17
  11. Xie S, Wu H, Wang Q, Kunicki J, Thomas RO, Hollingsworth RE, Cogswell J, Dai W
    Genotoxic stress-induced activation of Plk3 is partly mediated by Chk2. Cell cycle (Georgetown, Tex.) 2002 Nov-Dec;1(6):424-9
  12. Xie S, Xie B, Lee MY, Dai W
    Regulation of cell cycle checkpoints by polo-like kinases. Oncogene 2005 Jan 10;24(2):277-86
  13. Kawabe T
    G2 checkpoint abrogators as anticancer drugs. Molecular cancer therapeutics 2004 Apr;3(4):513-9
  14. Taylor WR, Stark GR
    Regulation of the G2/M transition by p53. Oncogene 2001 Apr 5;20(15):1803-15
  15. Xie S, Wu H, Wang Q, Cogswell JP, Husain I, Conn C, Stambrook P, Jhanwar-Uniyal M, Dai W
    Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. The Journal of biological chemistry 2001 Nov 16;276(46):43305-12
  16. Oren M, Damalas A, Gottlieb T, Michael D, Taplick J, Leal JF, Maya R, Moas M, Seger R, Taya Y, Ben-Ze'Ev A
    Regulation of p53: intricate loops and delicate balances. Annals of the New York Academy of Sciences 2002 Nov;973:374-83
  17. Melchior F, Hengst L
    SUMO-1 and p53. Cell cycle (Georgetown, Tex.) 2002 Jul-Aug;1(4):245-9
  18. Maeda T, Sim AB, Leedel DA, Chua PP, Chomey EG, Luong L, Tron VA
    UV induces GADD45 in a p53-dependent and -independent manner in human keratinocytes. Journal of cutaneous medicine and surgery 2003 Mar-Apr;7(2):119-23
  19. Smits VA, Klompmaker R, Vallenius T, Rijksen G, Mäkela TP, Medema RH
    p21 inhibits Thr161 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint. The Journal of biological chemistry 2000 Sep 29;275(39):30638-43
  20. Jin S, Antinore MJ, Lung FD, Dong X, Zhao H, Fan F, Colchagie AB, Blanck P, Roller PP, Fornace AJ Jr, Zhan Q
    The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. The Journal of biological chemistry 2000 Jun 2;275(22):16602-8
  21. Li J, Wang Y, Sun Y, Lawrence TS
    Wild-type TP53 inhibits G(2)-phase checkpoint abrogation and radiosensitization induced by PD0166285, a WEE1 kinase inhibitor. Radiation research 2002 Mar;157(3):322-30
  22. Liu F, Stanton JJ, Wu Z, Piwnica-Worms H
    The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex. Molecular and cellular biology 1997 Feb;17(2):571-83

  1. Sancar A, Lindsey-Boltz LA, Unsal-Kaçmaz K, Linn S
    Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual review of biochemistry 2004;73:39-85
  2. Bakkenist CJ, Kastan MB
    DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003 Jan 30;421(6922):499-506
  3. Zhao H, Watkins JL, Piwnica-Worms H
    Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proceedings of the National Academy of Sciences of the United States of America 2002 Nov 12;99(23):14795-800
  4. Peng A, Chen PL
    NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. The Journal of biological chemistry 2003 Mar 14;278(11):8873-6
  5. Xu X, Stern DF
    NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Oct;17(13):1842-8
  6. Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP
    Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. Genes & development 2002 Mar 1;16(5):583-93
  7. Stucki M, Jackson SP
    MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes. DNA repair 2004 Aug-Sep;3(8-9):953-7
  8. Cortez D, Guntuku S, Qin J, Elledge SJ
    ATR and ATRIP: partners in checkpoint signaling. Science (New York, N.Y.) 2001 Nov 23;294(5547):1713-6
  9. Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC
    BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nature genetics 2002 Mar;30(3):285-9
  10. Jiang K, Pereira E, Maxfield M, Russell B, Goudelock DM, Sanchez Y
    Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345. The Journal of biological chemistry 2003 Jul 4;278(27):25207-17
  11. Xie S, Wu H, Wang Q, Kunicki J, Thomas RO, Hollingsworth RE, Cogswell J, Dai W
    Genotoxic stress-induced activation of Plk3 is partly mediated by Chk2. Cell cycle (Georgetown, Tex.) 2002 Nov-Dec;1(6):424-9
  12. Xie S, Xie B, Lee MY, Dai W
    Regulation of cell cycle checkpoints by polo-like kinases. Oncogene 2005 Jan 10;24(2):277-86
  13. Kawabe T
    G2 checkpoint abrogators as anticancer drugs. Molecular cancer therapeutics 2004 Apr;3(4):513-9
  14. Taylor WR, Stark GR
    Regulation of the G2/M transition by p53. Oncogene 2001 Apr 5;20(15):1803-15
  15. Xie S, Wu H, Wang Q, Cogswell JP, Husain I, Conn C, Stambrook P, Jhanwar-Uniyal M, Dai W
    Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. The Journal of biological chemistry 2001 Nov 16;276(46):43305-12
  16. Oren M, Damalas A, Gottlieb T, Michael D, Taplick J, Leal JF, Maya R, Moas M, Seger R, Taya Y, Ben-Ze'Ev A
    Regulation of p53: intricate loops and delicate balances. Annals of the New York Academy of Sciences 2002 Nov;973:374-83
  17. Melchior F, Hengst L
    SUMO-1 and p53. Cell cycle (Georgetown, Tex.) 2002 Jul-Aug;1(4):245-9
  18. Maeda T, Sim AB, Leedel DA, Chua PP, Chomey EG, Luong L, Tron VA
    UV induces GADD45 in a p53-dependent and -independent manner in human keratinocytes. Journal of cutaneous medicine and surgery 2003 Mar-Apr;7(2):119-23
  19. Smits VA, Klompmaker R, Vallenius T, Rijksen G, Mäkela TP, Medema RH
    p21 inhibits Thr161 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint. The Journal of biological chemistry 2000 Sep 29;275(39):30638-43
  20. Jin S, Antinore MJ, Lung FD, Dong X, Zhao H, Fan F, Colchagie AB, Blanck P, Roller PP, Fornace AJ Jr, Zhan Q
    The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. The Journal of biological chemistry 2000 Jun 2;275(22):16602-8
  21. Li J, Wang Y, Sun Y, Lawrence TS
    Wild-type TP53 inhibits G(2)-phase checkpoint abrogation and radiosensitization induced by PD0166285, a WEE1 kinase inhibitor. Radiation research 2002 Mar;157(3):322-30
  22. Liu F, Stanton JJ, Wu Z, Piwnica-Worms H
    The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex. Molecular and cellular biology 1997 Feb;17(2):571-83

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