Serine/threonine-protein kinase ATR

Definition:

Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication. Positively regulates the restart of stalled replication forks following activation by the KHDC3L-OOEP scaffold complex (By similarity).

References:

[1]. Anne M Casper, et al. ATR regulates fragile site stability. Cell. 2002 Dec 13;111(6):779-89. [Content Brief]

[2]. D Cortez, et al. ATR and ATRIP: partners in checkpoint signaling. Science. 2001 Nov 23;294(5547):1713-6. [Content Brief]

[3]. Shunsuke Hanaki, et al. UV-induced activation of ATR is mediated by UHRF2. Genes Cells. 2021 Jun;26(6):447-454. [Content Brief]

[4]. Ester M Hammond, et al. Hypoxia links ATR and p53 through replication arrest. Mol Cell Biol. 2002 Mar;22(6):1834-43. [Content Brief]

[5]. R S Tibbetts, et al. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 1999 Jan 15;13(2):152-7. [Content Brief]

[6]. Lee Zou, et al. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003 Jun 6;300(5625):1542-8. [Content Brief]

[7]. Peter Haahr, et al. Activation of the ATR kinase by the RPA-binding protein ETAA1. Nat Cell Biol. 2016 Nov;18(11):1196-1207. [Content Brief]

[8]. Ji Zhang, et al. Protein phosphatase 5 is required for ATR-mediated checkpoint activation. Mol Cell Biol. 2005 Nov;25(22):9910-9. [Content Brief]

[9]. Paul R Andreassen, et al. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004 Aug 15;18(16):1958-63. [Content Brief]

[10]. Thomas E Bass, et al. ETAA1 acts at stalled replication forks to maintain genome integrity. Nat Cell Biol. 2016 Nov;18(11):1185-1195. [Content Brief]

[11]. Yoonsung Kang, et al. Protein phosphatase 5 is necessary for ATR-mediated DNA repair. Biochem Biophys Res Commun. 2011 Jan 7;404(1):476-81. [Content Brief]

[12]. S Bao, et al. ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature. 2001 Jun 21;411(6840):969-74. [Content Brief]

[13]. R S Tibbetts, et al. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev. 2000 Dec 1;14(23):2989-3002. [Content Brief]

[14]. I M Ward, et al. Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J Biol Chem. 2001 Dec 21;276(51):47759-62. [Content Brief]

[15]. S T Kim, et al. Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem. 1999 Dec 31;274(53):37538-43. [Content Brief]

[16]. Q Liu, et al. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000 Jun 15;14(12):1448-59. [Content Brief]

[17]. Gemma K Alderton, et al. Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway. Hum Mol Genet. 2004 Dec 15;13(24):3127-38. [Content Brief]

[18]. Irene M Ward, et al. UV-induced ataxia-telangiectasia-mutated and Rad3-related (ATR) activation requires replication stress. J Biol Chem. 2004 Mar 12;279(11):9677-80. [Content Brief]

[19]. Sharon M Barr, et al. ATR kinase activity regulates the intranuclear translocation of ATR and RPA following ionizing radiation. Curr Biol. 2003 Jun 17;13(12):1047-51. [Content Brief]

[20]. David Cortez, et al. Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10078-83. [Content Brief]

[21]. C A Hall-Jackson, et al. ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK. Oncogene. 1999 Nov 18;18(48):6707-13. [Content Brief]

[22]. Yi Wang, et al. MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15387-92. [Content Brief]

[23]. W A Cliby, et al. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 1998 Jan 2;17(1):159-69. [Content Brief]

[24]. Keziban Unsal-Kaçmaz, et al. Quaternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activities. Mol Cell Biol. 2004 Feb;24(3):1292-300. [Content Brief]

[25]. J A Wright, et al. Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7445-50. [Content Brief]

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