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Ataxia telangiectasia & Rad3-related (ATR) or FRAP-related protein-1 (FRP1)

Function: - serine/threonine kinase - recognizes the substrate consensus sequence [ST]-Q - activates checkpoint signaling upon genotoxic stresses a) ionizing radiation b) ultraviolet light c) DNA replication stalling - role as DNA damage sensor - Binds to DNA, & to UV- damaged DNA with higher affinity - inhibits DNA replication & mitosis - promotes DNA repair, DNA recombination, apoptosis - phosphorylates BRCA1,CHEK1, H2AFX, MCM2, RAD17, RPA2, SMC1 & p53 which collectively inhibit DNA replication & mitosis & promote DNA repair, recombination & apoptosis - phosphorylates Ser-139 of histone variant H2AX/H2AFX at sites of DNA damage, thus regulating DNA damage response - autophosphorylates in vitro - required for FANCD2 ubiquitination - maintenance of fragile site stability & efficient regulation of centrosome duplication - forms an heterodimer with ATRIP - complexes with CHD4 and HDAC2 - interacts with BCR-ABL after genotoxic stress - interacts with EEF1E1 & CLSPN (enhanced by UV irradiation) - interacts with RAD17, MSH2 ,HDAC2 - present in a complex containing CHD4 & HDAC2 - present in a complex containing ATRIP & RPA-coated single-stranded DNA - activated by DNA - inhibited by BCR-ABL oncogene - slightly activated by ATRIP, forms heterodimer with ATRIP - inhibited by caffeine, wortmannin & LY294002 Structure: - belongs to the PI3/PI4-kinase family, ATM subfamily - contains 1 FAT domain - contains 1 FATC domain - contains 2 HEAT repeats - contains 1 PI3K/PI4K domain Compartment: - nucleus - depending on the cell type, can also be found in PML nuclear bodies - recruited to chromatin during S-phase - redistributes to discrete nuclear foci upon DNA damage, hypoxia or replication fork stalling Alternative splicing: named isoforms=2 Expression: - ubiquitous, with highest expression in testis. - Recruited to chromatin during S-phase. - Redistributes to discrete nuclear foci upon - DNA damage, - hypoxia - replication fork stalling. Pathology: - defects in ATR are a cause of Seckel syndrome.

Related

Seckel syndrome

General

serine/threonine kinase

Properties

SIZE: entity length = 2644 aa MW = 301 kD COMPARTMENT: cell nucleus STATE: active state MOTIF: HEAT repeat {799-835} HEAT repeat {1329-1365} FAT domain NAME: FAT domain SITE: 1640-2185 MOTIF: Tyr phosphorylation site binding site FOR-BINDING-OF: Paxillin PI3K/PI4K {2322-2567} FATC {2612-2644}

References

  1. OMIM :accession 601215
  2. Entrez Gene :accession 545
  3. UniProt :accession Q13535

Databases & Figures

OMIM correlations UniProt Q13535 PFAM correlations Entrez Gene 545 Kegg hsa:545 ATM/ATR downstream reactions