Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Ataxia Telangiectasia and Rad3-Related (ATR)

  • Poorwa Awasthi
  • Vipin Kumar Yadav
  • Manisha Dixit
  • Amit Kumar
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101789



Saccharomyces pombe – Rad3

Saccharomyces cerevisiae – Mec1p

Drosophila melanogaster – Mei-41

Historical Background

Ataxia Telangiectasia and Rad3-related (ATR) or FRAP-related protein-1 (FRP1) is a 2644 amino acid protein kinase, located on chromosome 3q23 (Cimprich et al. 1996), which has 10 alternatively transcribed variants. ATR belongs to the PIKK (phosphatidylinositol 3-kinase related kinase) family of kinases (reviewed in Kidiyoor et al. 2016). Hypomorphic mutations in the ATR gene are associated with a rare autosomal recessive disorder, Seckel syndrome (OMIM #210600), characterized by intrauterine growth retardation, dwarfism, microcephaly, and mental retardation (Ogi et al. 2012); with cutaneous telangiectasia; mild developmental anomalies of hair, teeth, and nails; and a predisposition to cancer, predominantly oropharyngeal, in infants (Tanaka et al. 2012). ATR is essential (Brown and Baltimore 2000) and binds ATRIP (ATR-interacting protein) for stability and functional activation (Awasthi et al. 2015).

ATR is an important regulator of DNA damage checkpoint pathways, which are conserved across species to help cells cope with genotoxic stress, both extrinsic (ultraviolet, infrared light, etc.) and intrinsic (replication stress and reactive oxygen species) (Awasthi et al. 2015). Proteins in this pathway regulate cell cycle progression at G1/S and G2/M transitions (a point at which progression to next cell cycle stage is stalled until DNA damage is repaired), providing cells time to repair DNA lesions by initiating the DNA damage response (DDR) (Awasthi et al. 2015). In the case of extensive damage, cells are directed to apoptosis by this pathway. In eukaryotes, ATR stabilizes stalled replication forks and helps in fork restart after replication stress and thereby maintains genome integrity. In addition, recent studies show the involvement of ATR in a wide range of cellular processes in response to other cell stress conditions such as thermal shock, osmotic stress, and mechanical stress. ATR localizes to organelles such as nuclei, centrosomes, nucleoli, and mitochondria (Kidiyoor et al. 2016).

Structure and Activation of ATR

The primary structure of ATR is similar to other PIKK family members and is composed of Huntingtin Elongation Factor 3, Alpha regulatory subunit of protein phosphatase 2A, TOR1 (HEAT) repeats, FKBP12-rapamycin complex-associated protein (FRAP), Ataxia Telangiectasia Mutated (ATM) and TRRAP (FAT) domain, Kinase Domain (KD), PIKK regulatory domain (PRD), and FAT C-terminal (FATC) domain (Fig. 1) (Awasthi et al. 2015). The N-terminal 45 tandem HEAT repeats are vital for ATR kinase activity, as even a small change in HEAT repeats can affect the kinase activity. For example, S1333A mutation results in hyperactive ATR kinase, even in the absence of TopBP1 (Luzwick et al. 2014). The ATRIP binding site, nuclear localization sequence, and a BH3-like domain are also present in the HEAT repeat region (Fig. 1). HEAT repeats act as elastic connectors that serve as sensors for mechanical stimulus and mediate protein-protein interaction (Awasthi et al. 2015). The FAT domain is responsible for the interaction of ATR with NEMO (NF-κB essential modulator). The ATR kinase domain shows maximum homology with the kinase domain of PI3 kinases, although unlike these, the ATR kinase domain lacks lipid kinase activity. It phosphorylates a number of proteins after activation. PRD is a 30-amino acid domain (Fig. 1), located between the kinase and the FATC domains, and is involved in TopBP1 binding. At the C-terminus, the 33-amino acid FATC is the most conserved domain among PIKK members (Fig. 1).
Ataxia Telangiectasia and Rad3-Related (ATR), Fig. 1

Structure of ATR: ATR is composed of 2644 amino acids with a giant HEAT repeat at N-terminus containing ATRIP-binding domain, NLS, and BH3-like domain. It is followed by FAT domain and kinase domain. Next to the kinase domain is PIKK regulatory domain (PRD). FATC domain is present at the C-terminal. Numbers above the arrow line are representing amino acids in respective domains. In HEAT repeats two helices are connected by linker loop

ATR is activated primarily in response to single strand DNA lesions that can be generated during DNA damage repair, by replication stress (caused by a number of drugs or genotoxic agents), RNA-DNA hybrids, repetitive DNA sequences (e.g., telomeres), or by oncogenes. A cascade of events following ssDNA formation activate the canonical ATR pathway to sense damage, regulate cell cycle progression, and activate DNA repair pathways or induce apoptosis (Awasthi et al. 2015) . ssDNA is first bound by the replication protein A(RPA) complex consisting of RPA70, RPA32, and RPA14 (Fig. 2); the RPA-ssDNA nucleofilament then recruits ATR/ATRIP to lesions (Fig. 2) and is activated through autophosphorylation at T1989 (Nam et al. 2011). Some studies nonetheless omit the absolute requirement for RPA after ATR activation following genotoxic stress (reviewed in Awasthi et al. 2015). The RPA-ssDNA-loaded ATR/ATIP complex then interacts with RAD9-RAD1-HUS1 (9-1-1complex) (Fig. 2). 9-1-1 is a clamp, loaded at the junction of ssDNA - dsDNA by the clamp loader complex RAD17 – RFC (replication factor C) in an RPA-assisted manner (Fig. 2). RAD9 phosphorylation at S387 in the 9-1-1 clamp aids binding of the BRCT (BRCA1 C-terminus) domain of topoisomerase 2-binding protein1 (TopBP1) to the ATR FATC domain (Fig. 2). TopBP1 has an ATR activation domain (AAD) that causes full ATR activation, after which ATR phosphorylates its substrates at consensus serine or threonine residues, followed by glutamine (SQ/TQ) (Kim et al. 1999). ATR-ATRIP complex binding to ssDNA can also be facilitated by prior binding of the MutSβ complex (comprised of Msh2 and Msh3 proteins, involved in mismatch repair) to hairpins in ssDNA. The MRE11-RAD50-NBS1 (MRN) complex, which detects double-strand DNA breaks, can also regulate ATR activation. The MRN complex is reported to be necessary for TopBP1 recruitment and to promote Chk1 phosphorylation (Duursma et al. 2013). In addition, some posttranslational modifications of the ATR activation complex protein, such as ubiquitination of RPA by pre-mRNA processing factor 19 (PRP19), assist in ATR-ATRIP binding to ssDNA-RPA nucleofilaments, and ATR activation SUMOylation of ATRIP by PIAS3 SUMO ligase also regulates ATR activation following DNA damage (Wu and Zou 2016). Deacetylation of ATRIP at lysine 32 by sirtuin2 (SIRT2) was recently shown to facilitate ATRIP-ATR accumulation at RPA-ssDNA nucleofilaments for ATR activation (Yazinski and Zou 2016).
Ataxia Telangiectasia and Rad3-Related (ATR), Fig. 2

Canonical activation of ATR: Single-stranded DNA generated by damage is bound by RPA (replication protein A). RPA-ssDNA nucleofilament facilitates ATR-ATRIP complex binding to damaged DNA. 9-1-1 complex (RAD9-RAD1-HUS1) is recruited at ssDNA-dsDNA junction by RAD17-RFC clamp loader. 9-1-1 helps in binding of TopBP1 (topoisomerase-binding protein 1) with ATR. TopBP1 interacts with ATR through its BRCT (BRCA1 C-terminus) domain. RHINO (RAD9, RAD1, HUS1 interacting nuclear orphan) also mediates TopBP1 and ATR binding. ETAA1 also activates ATR by binding to RPA-ssDNA complex. (S SUMOylation, P Phosphorylation, Ub Ubiquitination)

ATR Signaling

ATR signaling is fundamental during DNA replication in the S-phase of cell cycle; specifically, it stabilizes the replication fork, helps in fork restart after replication stress, prevents fragile site expression, influences replication origin firing, and maintains coordination between replication and transcription (Kidiyoor et al. 2016). ATR acts mainly by phosphorylating Chk1 at S345 and S317 (active state), which in turn phosphorylates other effectors as Cdc25A (an inhibitor phosphatase), priming its degradation (Fig. 3). Unphosphorylated Cdc25A removes a phosphate group from CyclinE-Cdk2 and CyclinA-Cdk1 and allows cell cycle progression. Cdc25A degradation inhibits its association with Cycin A-Cdk1, CyclinB-Cdk1, and Cyclin E-Cdk2 and leads to accumulation of inactivated Cyclin-Cdk and thus cell cycle arrest at the G1/S checkpoint (Fig. 2). To maintain this arrest, ATR phosphorylates p53 either directly at Ser 15 or indirectly via pChk1 at Ser 20, preventing its nuclear export and degradation.
Ataxia Telangiectasia and Rad3-Related (ATR), Fig. 3

Canonical ATR signaling: Following DNA damage ATR phosphorylates and activates Chk1. pChk1 phosphorylates Cdc25A phosphatase and targets it for degradation. In absence of phosphatase CDK2-CyclinE/A complex remains in phosphorylated and inactivated form with a consequence of cell cycle arrest at G1/S transition. To maintain arrest, pChk1 phosphorylates and stabilizes p53. P53 activates p21 transcription. p21 binds and inactivates CyclinD-CDK4 complex. Inactivated Cyclin-CDK cannot phosphorylate Rb (Retinoblastoma protein). Unphosphorylated Rb remains bound with E2F transcription factor. Chk1 inhibits Dbf4/Cdc7 complex (DDK-Dbf4-dependent kinase) by phosphorylating Dbf4. Inactivated DDK cannot recruit Cdc45 (a protein required for polymerase loading at origin of replication) at replication origins. To slowdown the replication initiation, Chk1 phosphorylates Treslin (a protein required for Cdc45 loading at replication origins) and inhibits Cdc45 binding with TopBP1

Phosphorylated p53 initiates p21 transcription, which inhibits Cdk2/CyclinE and thus maintains G1/S arrest. p21 also regulates the Cdk4/CyclinD complex to inhibit progression through G1 to cell cycle S-phase (Fig. 4). pChk1 phosphorylation downregulates both the Cdc7/Dbf4 complex and Treslin, which assists Cdc45 recruitment to chromatin and thus inhibits origin firing during the intra-S phase checkpoint (Awasthi et al. 2015). Inhibition of ATR results in an aberrant increase in origin firing. ATR also helps to restart a stalled replication fork by phosphorylating various substrates such as BRCA1, NBS1, and SMARCAL1. In a multistep process, ATR maintains fork structure, phosphorylates and inhibits SMARCAL1 (SMARCA-like protein; an annealing helicase that reverses the replication fork and aids DSB formation by the SLX - endonuclease complex), thereby preventing fork collapse. Increased fork collapse is reported in ATR-deficient cells (Yazinski and Zou 2016). ATR also has a major role in mitosis; its loss leads to premature mitosis entry as well as chromosome fragmentation during mitosis.
Ataxia Telangiectasia and Rad3-Related (ATR), Fig. 4

Noncanonical ATR signaling: Stress induces ATR activation in nucleolus. Upon activation ATR relocalizes to nucleolus and nucleolar cap that forms due to stress. ATR activation results in Chk1 and p53 phosphorylation, increased p21 expression, and cell cycle arrest. rRNA transcription is inhibited by ATR activation in nucleolus by TopBP1 overexpression. In centrosome, ATR is phosphorylated at S-428. During extended S-phase delay, pChk1 phosphorylates CDK2 that results in centrosomal overduplication. Nuclear envelope has OMM (outer nuclear membrane) and INM (inner nuclear membrane) lined inside with nuclear lamina. In normal conditions, ATR is distributed in the nucleus. Following stress it localizes at the envelope. Topological stress generated during prophase (where nuclear envelope is broken down and chromatin condensation begins to start) recruits ATR at NE. Change in membrane fluidity (by insertion of polyunsaturated phosphatidylcholine) activates ATR at NE. Mechanical stress caused by actin cytoskeleton stretching, transduces signal through LINC complex to activate ATR. ATR either phosphorylates Chk1 or p53 to arrest cell cycle. Viral protein R (VPR) by disrupting NE activates ATR resulting in G2 arrest of cell cycle. Following UV, DAPK phosphorylates and inhibits PIN1 in mitochondria. In absence of PIN1 activity, cis-ATR localizes to mitochondria and binds to tBID through BH3-like domain (discussed in Fig. 1). tBID inhibits BAX (a protein that regulates apoptosis by promoting release of cytochrome C from mitochondria) and thus helps in cell survival

Since ATR was discovered as a gene involved in cell-cycle checkpoint activation following DNA damage, its roles in response to other types of cell stress were overlooked in past decades. Recent findings suggest ATR activation after osmotic, mechanical stress or thermal shock, and that it localizes to various cell organelles such as mitochondria, centrosomes, and nucleoli, indicating a potential role for ATR at these sites as well (Kidiyoor et al. 2016). In any case, much remains to be understood about ATR activation mechanisms in these scenarios.
  • ATR in mitochondria: ATR has an antiapoptotic role after cell exposure to UV light. ATR binds to truncated-BID (t-BID BH3 interacting-domain death agonist) through its BH3-like domain, thereby inhibiting tBID-dependent recruitment of Bax (proapoptotic Bcl2-associated X) to mitochondria, and suppresses cytochrome C release and thus apoptosis (Fig. 2). In the nucleus, ATR remains predominantly in the trans-ATR form. While mitochondrial ATR is in cis-ATR form upon exposure to DNA damaging agents as UV (Hilton et al. 2015). In normal conditions, this binding is inhibited by ATR cis-to-trans isomerization at the phosphorylated Ser428 Pro429 motif by PIN1 (peptidylprolyl cis/trans isomerase NIMA-interacting 1) (Fig. 2). Isomerization buries the BH3-like domain of ATR through conformational changes, thereby preventing its interaction with tBID. This function of mitochondria-specific ATR (mtATR) is ATRIP-independent and might be a reason for the very low checkpoint activity of cytoplasmic ATR (Hilton et al. 2015). These findings are relevant, as they might offer an opportunity to inhibit ATR selectively for the development of new therapeutic approaches to cancer.

  • ATR at the nuclear envelope: The current notion is that the nuclear envelope (NE) is disrupted only during mitosis, but there is increasing evidence that the NE can be ruptured transiently during interphase (Lammerding and Wolf 2016). Topological constraints of chromatin or cytoskeletal changes exert constant mechanical force on the NE. To maintain nuclear homeostasis in these conditions, the NE has an important function in transducing these signals to rest of the nucleus with the help of checkpoint and NE proteins (Fig. 2). Recent findings suggest an ATR role in response to any NE alteration that ultimately poses a threat to genome integrity (Kidiyoor et al. 2016).

  • ATR inside nucleoli: The nucleoli are centers of biogenesis of multiple RNP; they regulate cell cycle control, apoptosis, viral infection, DNA replication, and repair. As a result, the nucleolus is a central element in coordinating the stress response, regulating cell growth, promoting survival, and recovery from stress. The ATR has p53-dependent and independent functions in the nucleolus. It induces cell cycle arrest by phosphorylating p53 following thermal shock (Fig. 2). Actinomycin D activates ATR in nucleoli, and CX-5461 (a very specific inhibitor of Pol I transcription initiation) activates ATM/ATR signaling within 30 minutes independently of p53. ARF tumor suppressor (p14ARF) activates ATR upon induction which results in inactivation of RelA (a component of NF-κB) (Quin et al. 2016). CX-5461 induces chromatin changes at the rDNA repeats. Nucleolar segregation is also reported by TopBP1-induced ATR activation in the nucleolus, which does not lead to cell cycle arrest but rather inhibits rRNA transcription and reorganization of nucleolar compartments, similar to that is caused by Actinomycin D (Sokka et al. 2015).

  • ATR at centrosomes: CDK1-cyclin B activation at centrosomes and inside the nucleus is essential for mitosis entry and is controlled by CDC25 phosphatase. This phosphatase is reported to be phosphorylated, and thus inhibited, by Chk1 and Chk2 kinases after a DNA damage response. During extended S-phase delay, cyclin-dependent kinase-2 (CDK2) activity is upregulated by Chk1-dependent phosphorylation at Thr160, causing overduplication of centrosomes. Polo-like kinase (PLK1), an ATR/ATM substrate, regulates centrosome cohesion and centriole disengagement. Following DNA damage, PLK1 is inhibited, which blocks NEK2 activation and impedes centrosome separation (Fig. 2). CEP164, a distal appendage protein, is described as an ATR/ATM interactor, and its knockdown impairs activation of DDR proteins (Sivasubramaniam et al. 2008). PCM is also affected by DNA-damaging agents. In the absence of MCPH1, a Chk1 interactor, PCM expansion is enhanced. Homozygous mutation in the pericentrin gene (PCNT) gives rise to primordial dwarfism syndrome, similar to Seckel syndrome. In addition, phosphorylation of ATR substrates is impaired, and there is G2/M checkpoint arrest in PCNT-mutant cells (Mullee and Morrison 2016). The understanding of ATR/Chk1 axis at centrosomes remains at nascent stage, and whether centrosomal effects of DNA damage are due to cell cycle deregulation or are a spatiotemporal response to genotoxic stress requires further study.

ATR and Cancer

ATR/Chk1 bears a mononucleotide microsatellite repeat region in their coding sequences, which are mutational hotspots in tumors. Mutations in these areas result in expression of truncated ATR/Chk1 protein with defective mismatch repair. Haplo insufficiency in ATR expression promotes tumorigenesis. ATR/Chk1 mutation is reported in many cancer types including colon, endometrial, stomach, breast, colorectal, and skin cancers. Somatic mutation in ATR (exon 10, (A) 10 mononucleotide) with defective mismatch repair was reported in endometrioid endometrial cancer (Zighelboim et al. 2009), and in some sporadic colorectal and gastric cancers, a Chk1 frameshift mutation (exon 7, (A)9) was also reported (Lewis et al. 2007). In preclinical studies, ATR/Chk1 inhibits cancer development rather than promoting it, and ATR blockade increases replication stress and promotes senescence and apoptosis (Murga et al. 2011). In cancer therapy, genotoxic drugs and radiotherapy activate the cell cycle checkpoint and provide sufficient time for DNA repair, resulting in tumor cell survival, whereas use of a pharmacological ATR inhibitor increases chemotherapy effectiveness.

Oncogene (Cyclin E, Myc, and RAS)-driven cancers have a much higher level of replication stress than normal cells, and oncogene activation can increase origin firing and replisome collision within transcription machinery. ATM/Chk2 and ATR/Chk1 are two major signaling pathways that maintain genomic integrity during DDR and act as a barrier to tumor growth. In normal cells, G1 and S/G2 cell cycle checkpoints are functional. Exposures to genotoxic agents increase the replication stress-load, leading to checkpoint activation via ATM/p53- and ATR/Chk1-dependent manner. ATM/p53 signaling is abrogated in cancer cells, resulting in loss of the G1 checkpoint, so that the cells only depend on the S/G2 (ATR/Chk1 pathway) checkpoint to attenuate this stress load. ATR inhibition increases the DNA damage load in cancer cells, leading to apoptosis or permanent cell senescence, at difference from normal cells in which the G1 checkpoint is unaffected. ATR inhibition should thus selectively kill or sensitize cancer cells, by exploiting a concept of synthetic lethality. Selective ATR inhibitors are shown in Table 1.
Ataxia Telangiectasia and Rad3-Related (ATR), Table 1

List of ATR inhibitors, their target and potency

S. No.

Compound name


ATR potency IC50




1.8 μM




10 nM




0.014 μM




0.021 μM




>100 μM




1.1 mM




0.85 μM


Nu 6027


0.1 μM


Schisandrin B


7.25 μM




0.62 μM




4.5 nM



ATR (phase I clinical trials: NCT02157792)

0.019 μM



ATR (phase I clinical trials: NCT02223923)

1 nM


ATR is a eukaryotic gene initially described as a cell cycle checkpoint protein. With the advance of new techniques, it was found to have a crucial role outside the nucleus, in the nuclear envelope, mitochondria, centrosome, and nucleolus. ATR is activated in response to ssDNA damage and binds to the lesion along with its regulatory partner ATRIP, and thus mediates its signaling via phosphorylation of many other proteins. As a checkpoint protein, it halts the cell cycle in G1/S and G2/M if DNA is damaged. Recent findings suggest that, in addition to these canonical functions, it has a role that is independent of DNA damage. Defining additional ATR substrates and its interactors would help to understand role of ATR in stress as well as in physiological conditions. Knowledge of still-unknown substrates could provide a means for better regulation of the cell cycle. New techniques will enable the study of the role of ATR in transcription regulation, in DNA damage response signaling, as well as at locations where it has not yet been reported. This would be of clinical relevance in the field of cancer therapies as well as for other pathological conditions to which ATR is related.


Acknowledgment and Contribution

P.A., V.Y., M.D., and A.K. wrote the manuscript; P.A. made the figures and tables. P.A. and V.Y. held a predoctoral fellowship from the Council of Scientific and Industrial Research (CSIR), and M.D. held a predoctoral fellowship from the Department of Biotechnology (DBT). A.K. lab is funded by the CSIR Indepth, Epigentics in health and disease network projects, and DST, Govt. of India. CSIR manuscript communication number: 3432.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Poorwa Awasthi
    • 1
    • 2
  • Vipin Kumar Yadav
    • 1
    • 2
  • Manisha Dixit
    • 1
    • 2
  • Amit Kumar
    • 1
    • 2
  1. 1.Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment GroupCSIR-Indian Institute of Toxicology ResearchLucknowIndia
  2. 2.Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR CampusLucknowIndia