scholarly journals Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent

2018 ◽  
Vol 61 (22) ◽  
pp. 9889-9907 ◽  
Author(s):  
Kevin M. Foote ◽  
J. Willem M. Nissink ◽  
Thomas McGuire ◽  
Paul Turner ◽  
Sylvie Guichard ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Anticancer Agent ◽  
Potent Inhibitor ◽  
Ataxia Telangiectasia Mutated ◽  
Atr Kinase

scholarly journals Tethering DNA Damage Checkpoint Mediator Proteins Topoisomerase IIβ-binding Protein 1 (TopBP1) and Claspin to DNA Activates Ataxia-Telangiectasia Mutated and RAD3-related (ATR) Phosphorylation of Checkpoint Kinase 1 (Chk1)

2011 ◽  
Vol 286 (22) ◽  
pp. 19229-19236 ◽  
Author(s):  
Laura A. Lindsey-Boltz ◽  
Aziz Sancar
Keyword(s):  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Mammalian Cells ◽  
Binding Protein ◽  
Effector Proteins ◽  
Ataxia Telangiectasia Mutated ◽  
Checkpoint Kinase ◽  
Atr Kinase

The ataxia-telangiectasia mutated and RAD3-related (ATR) kinase initiates DNA damage signaling pathways in human cells after DNA damage such as that induced upon exposure to ultraviolet light by phosphorylating many effector proteins including the checkpoint kinase Chk1. The conventional view of ATR activation involves a universal signal consisting of genomic regions of replication protein A-covered single-stranded DNA. However, there are some indications that the ATR-mediated checkpoint can be activated by other mechanisms. Here, using the well defined Escherichia coli lac repressor/operator system, we have found that directly tethering the ATR activator topoisomerase IIβ-binding protein 1 (TopBP1) to DNA is sufficient to induce ATR phosphorylation of Chk1 in an in vitro system as well as in vivo in mammalian cells. In addition, we find synergistic activation of ATR phosphorylation of Chk1 when the mediator protein Claspin is also tethered to the DNA with TopBP1. Together, these findings indicate that crowding of checkpoint mediator proteins on DNA is sufficient to activate the ATR kinase.

scholarly journals Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM

2004 ◽  
Vol 64 (24) ◽  
pp. 9152-9159 ◽  
Author(s):  
Ian Hickson ◽  
Yan Zhao ◽  
Caroline J. Richardson ◽  
Sharon J. Green ◽  
Niall M. B. Martin ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Specific Inhibitor ◽  
Ataxia Telangiectasia Mutated ◽  
Identification And Characterization

scholarly journals Regulation of ATR activity by the RNA polymerase II phosphatase PNUTS-PP1

2018 ◽  
Author(s):  
Helga B. Landsverk ◽  
Lise E. Sandquist ◽  
Gro Elise Rødland ◽  
Beata Grallert ◽  
Laura Trinkle-Mulcahy ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Ataxia Telangiectasia ◽  
Replication Stress ◽  
Dependent Manner ◽  
Ataxia Telangiectasia Mutated ◽  
Carboxy Terminal Domain ◽  
Key Factor ◽  
Carboxy Terminal ◽  
Atr Kinase ◽  
Insight Into

AbstractAtaxia telangiectasia mutated and Rad3-related (ATR) kinase is a key factor activated by DNA damage and replication stress. Here, we show that ATR signaling is increased in human cells after depletion of the RNAPII phosphatase PNUTS-PP1, which dephosphorylates RNAPII on Ser 5 of its carboxy-terminal domain (CTD) (pRNAPII S5). Increased ATR signaling was observed in the presence and absence of ionizing radiation or replication stress and even in G1 phase after depletion of PNUTS. Vice versa, ATR signaling was reduced, in a PNUTS dependent manner, after inhibition of the CDK7 kinase mediating pRNAPII S5. Furthermore, CDC73, a well-known RNAPII-CTD binding protein, was required for the high ATR signaling after depletion of PNUTS and co-immunoprecipitated with RNAPII and ATR. These results suggest a novel pathway involving RNAPII, PNUTS-PP1 and CDC73 in ATR signaling and give new insight into the diverse functions of ATR.

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