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Gene Section
Review
ATR (ataxia telangiectasia and Rad3 related)
Mary E Gagou, Mark Meuth
Institute for Cancer Studies, The University of Sheffield, Medical School, Beech Hill Road, Sheffield, S10
2RX, UK (MEG, MM)
Published in Atlas Database: May 2010
Online updated version: http://AtlasGeneticsOncology.org/Genes/ATRID728ch3q23.html
DOI: 10.4267/2042/44954
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
DNA damage protein sensors, mediators and effectors,
DNA repair proteins, proteins of replisome and
chromatin remodelling as well as centrosomal proteins.
ATR function is essential for cell viability and
disruptions of ATR signalling cause genomic
instability. Mutations in ATR gene are rare and
compatible with life only when hypomorphic or
heterozygous. A clear link between disease and ATR
gene mutation is the Seckel syndrome, while ATR has
been proposed to serve as a haploinsufficient tumor
suppressor in some types of cell deficiencies and its
activation has been detected in most cancer
chemotherapies.
See also the Deep Insight: Ataxia-Telangiectasia and
variants.
Identity
Other names: FRP1, MEC1, SCKL, SCKL1
HGNC (Hugo): ATR
Location: 3q23
Local order
According to NCBI Map Viewer (ATR), genes
(pseudogenes and hypothetical proteins have been
excluded) flanking ATR in telomere to centromere
direction on 3q23 are: SLC9A9 (solute carrier family 9
(sodium/hydrogen exchanger), member 9), CHST2
(carbohydrate
(N-acetylglucosamine-6-O)
sulfotransferase 2), SR140 (U2-associated SR140
protein), PAQR9 (progestin and adipo Q receptor
family member IX), PCOLCE2 (procollagen Cendopeptidase enhancer 2), TRPC1 (transient receptor
potential cation channel, subfamily C, member 1),
PLS1 (plastin I (I isoform)), ATR.
Note
ATR is a serine/threonine kinase and belongs to the
phosphoinositide 3- kinase related protein kinases
(PIKKs), particularly to ATM (ataxia telangiectasia
mutated) subfamily. It functions to maintain genome
integrity by stabilizing replication forks and by
regulating cell cycle progression and DNA repair.
ATR, in a complex with its regulatory partner ATRIP
(ATR interacting protein), localises to stalled
replication forks responding to a variety of types of
replication stress and DNA damage. Recipients of ATR
signalling are a plethora of substrates among them
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2)
DNA/RNA
Note
The first human ATR cDNA full-length clone
(originally named FRP1, FRAP-related protein 1) was
isolated from a Jurkat T-cell cDNA library and
identified by its significant homology to other members
of the phosphatidylinositol kinase-related kinase
(PIKK) family. Evidence for the existence of two
alternative ATR transcripts, with differential tissue
expression, in the non-catalytic domain has been
reported, by using RT-PCR. Transcript variants
utilizing alternative polyadenylation signals are also
exist. ATR gene has recently been annotated in the
Ensembl database.
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ATR (ataxia telangiectasia and Rad3 related)
Gagou ME, Meuth M
Intron/Exon structure of the ATR gene (ENSG00000175054). There are two transcript isoforms of this gene, with 47 and 46 exons,
respectively, spanning to an area of 129.59 kb. Exons are illustrated with vertical lines and boxes (A, B). Diagram in panel B represents
only the exons' structure. Direction of transcription is shown by an arrow. The 6th exon that is missing from ATR isoform 2 is indicated
with an asterisk (A) or with blue colour box (B). Untranslated regions are in light pink, while coding regions are in deep pink. Start of
translation (ATG) and stop codon (TGA) are also indicated.
Forced expression of ATR inhibits MyoD function,
leading to loss of differentiation, as well as induces
cell-cycle abnormalities (increased aneuploidy and
elimination of IR-induced G1 arrest). Limited
expression of ATR or overexpression of kinase dead
forms of this protein increases cell sensitivity to a
variety of DNA damage agents and replication
inhibitors, such as ionizing radiation (IR), cis-platinum,
hydroxy urea (HU), methylmethanesulfonate (MMS)
and ultra violet (UV) irradiation, leading to significant
losses in checkpoint control and cell viability. Loss of
ATR results in DNA fragile site expression, a specific
type of genomic instability.
Description
47 exons spanning to 129.59 kb.
Transcription
Two isoforms: isoform ATR-201 (ENST00000350721)
(8248 bp) includes all 47 exons, while isoform ATR202 (ENST00000383101) (8056 bp) does not include
exon 6, deleting 192 nt (64 codons) from the mRNA.
The translation start site is in exon 1.
Protein
Note
ATR and ATM function in an overlapping, but nonredundant fashion, phosphorylating many of the same
substrates. However, and in contrast to ATM, ATR's
function is essential for cell viability. ATR-deficiency
at the organismal level affects normal development,
tissue homeostasis, and ageing.
Localisation
In the nucleus, where it is recruited to chromatin during
S-phase and redistributes to distinct foci upon DNA
damage, stalling of replication forks with replication
inhibitors or hypoxia. ATR has also been found in PML
(promyetocytic leukaemia protein) nuclear bodies of
some types of cells.
Kinase dead forms of ATR do not relocalize in
response to IR and block nuclear translocation of RPA
complex in a cell cycle-dependent manner.
Description
Isoform ATR-201 (ENSP00000343741): 2644 amino
acids (predicted MW 301365.74 Da).
Isoform ATR-202 (ENSP00000372581): 2580 aa
(predicted MW 294218.33 Da).
Biochemical studies of ATR protein do not distinguish
between the two different isoforms.
ATR protein contains a PI3/4 kinase catalytic domain,
1 FAT domain, 1 FATC domain, 1 UME domain, and 2
HEAT repeats.
Function
ATR essential maintains genome integrity by serving
multiple roles in the cellular response to DNA damage
and endogenous replication stress. It signals to regulate
the firing of replication origins, the repair of damaged
replication forks and to prevent the premature mitotic
entry. Moreover, it critically functions directly at the
sites of stalled forks by stabilizing components of the
replisome to ensure completion of replication during
recovery of stalled forks.
Expression
Isoform 1 has ubiquitous expression with highest levels
in testis. Isoform 2 has more specific expression (has
found in pancreas, liver and placenta while is not
detected in heart, testis and ovary).
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2)
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Gagou ME, Meuth M
replication stress in normal cycling cells as well as after
exposure to DNA damage agents.
ATR implication in centrosomal function via:
(a) Direct interaction with NBS1 (Nijmegen breakage
syndrome 1) and BRCA1 pathway.
(b) Signalling to Chk1 and control of centrosome
overduplication after DNA damage.
(c) Direct phosphorylation and delocalization from
centrosome of CEP63 in the presence of chromosomal
breaks.
ATR-mediated activation of S-phase checkpoint
ATR is activated during every S-phase and in response
to many different types of damage, including double
strand breaks (DSB), base adducts, crosslinks and
replication stress. The structural requirement for ATR
activation is a RPA-coated single-stranded DNA with a
5' double stranded primer junction. ATR recognition of
the above DNA structure depends upon a protein cofactor, ATRIP (ATR-interacting protein), that regulates
ATR localization and activation. The activity of ATRATRIP complex is directly stimulated by TOPBP1
(DNA topoisomerase II binding protein 1), which
recruitment to DNA is facilitated by the 9-1-1 (Rad9Rad1-Hus1) checkpoint clamp.
Activated ATR signals to coordinate cell cycle
transitions and repair through the phosphorylation of
numerous of substrates including RAD17, p53,
TopBP1 (via a feed-forward signalling loop that
amplifies ATR-mediated signals), the mediator protein
CEP164 and the downstream effector Chk1 (checkpoint
kinase 1), which is the best characterized target of the
ATR activity. Recombination proteins BRCA1 (breast
cancer susceptibility gene 1), WRN (Werner's
syndrome helicase), and BLM (Bloom's syndrome
helicase) are ATR sunstrates as well. ATR also
phosphorylates the Fanconi-anemia protein FANCD2
to regulate inter-strand crosslink repair as well as the
nucleotide excision repair protein XPA to regulate its
intracellular localization. Moreover, ATR interacts with
the mismatch repair protein MSH2 (mutS homolog 2)
to form a signalling module and regulate the
phosphorylation of Chk1 and SMC1 (structure
maintenance of chromosome 1). Upon replication stress
ATR
also
phosphorylates
the
Ser-139
of
H2AX/H2AFX, while is associated with the tyrosine
kinase oncogene BCR-ABL after genotoxic stress.
ATR-mediated stabilization of replication forks
ATR has a crucial role in the maintenance of functional
replication forks independent of its function in the
activation of Rad53 (yeast homolog of checkpoint
kinase 2). Among substrates of ATR on the replication
forks are the proteins RPA1, RPA2, MCM2-7
(minichromosome
maintenance
2-7)
complex,
MCM10, PCNA, replication factor C, Tim (Timeless)Tipin complex, SMARCAL1 (HARP)-a SNF2 ATPdependent annealing helicase, and several polymerases,
such as Pol alpha and Pol epsilon. Furthermore, a key
target of ATR-ATRIP complex is Claspin, and is
important both for S-phase checkpoint activation (via
regulation of Chk1 phosphorylation) but also for
replication forks stabilization (via interactions with Pol
epsilon) even in normal cycling cells. ATR is found
also associated with two components of the
nucleosome remodelling and deacetylating complex,
the chromodomain-helicase-DNA-binding protein 4
(CHD4) and the histone-deacetylase-2 (HDAC2).
ATR also functions to stabilize fragile sites. In effect of
all the above, the ATR's essential function for cell
viability may be to respond to abundant sources of
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2)
Homology
According to HomoloGene (NCBI), homologs of the
human ATR gene (NP_001175.2, 2644 aa) are the
followings:
- Chimpanzee (Pan troglodytes) XP_516792.2, 2646 aa
- Dog (Canis lupus familiaris) XP_534295.2, 2644 aa
- Cattle (Bos taurus) XP_581054.3, 2644 aa
- Rat (Rattus norvegicus) XP_001062084.1, 2166 aa
- Zebrafish (Danio rerio) XP_696163.3, 2638 aa
Mutations
Somatic
Single nucleotide substitutions have been described in
various types of carcinomas at total frequency 2%,
mostly in heterozygous form. In particular, missense
mutations have been found in the PI3/4 kinase catalytic
domain and in FAT domain of breast and lung cancers
respectively. Coding silent mutations have also been
detected in carcinomas of stomach, breast, skin and
central nervous system.
Implicated in
ATR haploinsufficiency in mismatch
repair (MMR)-deficient cancers
Note
Homozygous null mutations of ATR have not been
reported in human cancers even in late-stage malignant
cells and it is unlikely to exist given that mutations in
both alleles of ATR gene lead to cell lethality.
However, ATR gene has a potential increased
susceptibility to somatic mutations in tumors with
defective MMR, due to the presence of an A10
mononucleotide repeat in the exon 10 protein coding
region. In particular, clinical reports have demonstrated
that ATR is heterozygously mutated in certain types of
tumors with mismatch repair deficiencies, including
malignancies of the colon, the stomach and the
endometrium. Although, it is not well understood how
these mutations could contribute to the tumorigenic
process, lines of evidence suggest that ATR serves as a
haploinsufficient tumor suppressor in mismatch repairdeficient cells. Disruption of a single ATR allele gene
in MLH1-deficient background significantly increases
fragile site expression, chromosomal amplifications and
rearrangements. The above chromosomal instability
124
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Gagou ME, Meuth M
accompanied by hypersensitivity to genotoxic stress
agents, such as hydroxyurea. Furthermore, mice with
ATR+/- MLH1-/- genotype are more prone to early
tumor development compared with ATR+/- or MLH1/- counterparts. More recently has been reported that
the combined ATR haploinsufficiency and MMRdeficiency that lead to chromosomal instability in colon
cancer cells are also enhance the sensitivity of these
cells to chemotherapeutic agent 5-fluorouracil, a
standard treatment for colorectal cancers. The
mechanism by which this occurs remains unclear.
However, some findings suggest that MMR-deficient
cells with partial reduced ATR activity are more prone
to formation of DNA double strand breaks (DSBs).
Additionally, partial inhibition of ATR has been
reported to be significant for treatment of patients with
high-microsatellite instability (MSI, a class of genomic
instability clinically distinct from chromosome
instability that is the result of mutations in MMR
machinery) colorectal tumors increasing the diseasefree survival time.
Prognosis
Recent works have demonstrated that high-MSI
endometrioid endometrial cancers harboring ATR
mutations have worse survival compared to ATR wildtype high-MSI tumors, suggesting that the last ones
might also have an improved prognosis compared to
microsatellite stable (MSS) endometrial tumors.
However, the prognostic significance of ATR
mutations in MMR deficient cancers remains to be
clarified.
Cytogenetics
ATR partial knockdown in colon cancer cell lines with
defective MMR leads to the formation of chromosomal
breaks and gaps, chromosome bridges and micronuclei,
as well as to the formation of supernumerary
centrosomes.
sensitivity to DNA replication fork stalling (measured
as nuclear fragmentation and micronucleus formation),
impaired phosphorylation of ATR substrates, defective
G2/M arrest and supernumerous mitotic centrosomes.
Impaired ATR signalling is also characteristic of cells
derived from other disorders with microcephaly and
growth delay such as pericentrin-mutated Seckel
syndrome (PCNT-SS), primary autosomal recessive
microcephaly (MCPH) and Nijmegen breakage
syndrome.
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Note
Seckel syndrome is a rare autosomal recessive disorder
characterised by severe intrauterine growth retardation,
profound microcephaly, dwarfism, mental retardation
and isolated skeletal abnormalities. At least four
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ATR-dependent DNA damage signalling. The first
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Neitzel H,
Krämer A.
entry via
2009 Jun
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