Serine/threonine-protein kinase ATR

UniProt Q13535 Organism Homo sapiens Gene ATR, FRP1 EC 2.7.11.1

Also known as: ATR, FRP1

Function

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, RBBP8, 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. Acts as a regulator of the S-G2 transition by restricting the activity of CDK1 during S-phase to prevent premature entry into G2. Acts as a regulator of the nuclear envelope integrity in response to DNA damage and stress. Acts as a mechanical stress sensor at the nuclear envelope: relocalizes to the nuclear envelope in response to mechanical stress and mediates a checkpoint via phosphorylation of CHEK1. Also promotes nuclear envelope rupture in response to DNA damage by mediating phosphorylation of LMNA at 'Ser-282', leading to lamin disassembly. Involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability and catalyzing phosphorylation of LMNA at 'Ser-395', priming LMNA for subsequent phosphorylation by CDK1 and micronuclei envelope rupture. The rupture of micronuclear envelope triggers the cGAS-STING pathway thereby activating the type I interferon response and innate immunity. Positively regulates the restart of stalled replication forks following activation by the KHDC3L-OOEP scaffold complex (By similarity).

Classification

Family (Pfam): PF02259 FAT, PF02260 FATC, PF23593 HEAT_ATR, PF25030 M-HEAT_ATR, PF25032 N-HEAT_ATR, PF00454 PI3_PI4_kinase, PF08064 UME
InterPro: ARM-like, ARM-type_fold, ATR-like_M-HEAT, ATR-like_N-HEAT, DDR_Repair_Kinase, FATC_dom, HEAT_ATR, HEAT_type_2, Kinase-like_dom_sf, PI3/4_kinase_cat_dom, PI3/4_kinase_cat_sf, PI3/4_kinase_CS, PIK-rel_kinase_FAT, PIK_FAT, TPR-like_helical_dom_sf, UME
Functional cluster: Zinc-Finger & Chromatin Regulatory Proteins

Experimental structures · PDB · 9

5YZ0 EM 4.70A
9L40 EM 2.87A
9L43 EM 3.83A
9L45 EM 3.95A
9L46 EM 6.29A
9L4B EM 3.20A
9L4C EM 4.06A
9L4D EM 3.79A
9L4F EM 6.22A

A predicted model is available from AlphaFold.

Gene Ontology · 41

Disease associations

Seckel syndrome 1 MONDO:0008869
familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome MONDO:0013806

Drugs targeting this protein · 4

BERZOSERTIB inhibitor
CERALASERTIB inhibitor
ELIMUSERTIB inhibitor
M4344 inhibitor

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

ATR-interacting protein 4 shared papers
Protein kinase rad3 1 shared papers
Ewing's tumor-associated antigen 1 3 shared papers
Serine/threonine-protein kinase ATR 2 shared papers
Serine/threonine-protein kinase Chk1 4 shared papers
Serine-protein kinase ATM 8 shared papers
Prelamin-A/C 2 shared papers
E3 ubiquitin-protein ligase UHRF2 1 shared papers
Replication protein A 32 kDa subunit 3 shared papers
Serine/threonine-protein phosphatase 5 2 shared papers
DNA topoisomerase 2-binding protein 1 2 shared papers
DNA endonuclease RBBP8 1 shared papers

Literature · 58 cited papers

DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of lamin A/C. Mol. Cell · 2023
ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei. Mol. Cell · 2023
UV-induced activation of ATR is mediated by UHRF2. Genes Cells · 2021
An intrinsic S/G2 checkpoint enforced by ATR. Science · 2018
ETAA1 acts at stalled replication forks to maintain genome integrity. Nat. Cell Biol. · 2016
Activation of the ATR kinase by the RPA-binding protein ETAA1. Nat. Cell Biol. · 2016
ATR mediates a checkpoint at the nuclear envelope in response to mechanical stress. Cell · 2014
Activation of DSB processing requires phosphorylation of CtIP by ATR. Mol. Cell · 2013
Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
Germline mutation in ATR in autosomal- dominant oropharyngeal cancer syndrome. Am. J. Hum. Genet. · 2012
ATR autophosphorylation as a molecular switch for checkpoint activation. Mol. Cell · 2011
Thr-1989 phosphorylation is a marker of active ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. J. Biol. Chem. · 2011
… and 46 more in the literature graph

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