Chemical strategies for development of ATR inhibitors

ATR protein kinase is one of the key players in maintaining genome integrity and coordinating of the DNA damage response and repair signalling pathways. Inhibition of ATR prevents signalling from stalled replication forks and enhances the formation of DNA damage, particularly under conditions of replication stress present in cancers. For this reason ATR/CHK1 checkpoint inhibitors can potentiate the effect of DNA cross-linking agents, as evidenced by ATR inhibitors recently entering human clinical trials. This review aims to compile the existing literature on small molecule inhibitors of ATR, both from academia and the pharmaceutical industry, and will provide the reader with a comprehensive summary of this promising oncology target.

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Regulation of Rtt107 Recruitment to Stalled DNA Replication Forks by the Cullin Rtt101 and the Rtt109 Acetyltransferase

Molecular Biology of the Cell ◽

10.1091/mbc.e07-09-0961 ◽

2008 ◽

Vol 19 (1) ◽

pp. 171-180 ◽

Cited By ~ 45

Author(s):

Tania M. Roberts ◽

Iram Waris Zaidi ◽

Jessica A. Vaisica ◽

Matthias Peter ◽

Grant W. Brown

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Replication Forks ◽

Chromatin Binding ◽

Direct Role ◽

Repair Enzymes ◽

Damage Response ◽

Stalled Replication Forks

RTT107 (ESC4, YHR154W) encodes a BRCA1 C-terminal domain protein that is important for recovery from DNA damage during S phase. Rtt107 is a substrate of the checkpoint kinase Mec1, and it forms complexes with DNA repair enzymes, including the nuclease subunit Slx4, but the role of Rtt107 in the DNA damage response remains unclear. We find that Rtt107 interacts with chromatin when cells are treated with compounds that cause replication forks to arrest. This damage-dependent chromatin binding requires the acetyltransferase Rtt109, but it does not require acetylation of the known Rtt109 target, histone H3-K56. Chromatin binding of Rtt107 also requires the cullin Rtt101, which seems to play a direct role in Rtt107 recruitment, because the two proteins are found in complex with each other. Finally, we provide evidence that Rtt107 is bound at or near stalled replication forks in vivo. Together, these results indicate that Rtt109, Rtt101, and Rtt107, which genetic evidence suggests are functionally related, form a DNA damage response pathway that recruits Rtt107 complexes to damaged or stalled replication forks.

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A model of DNA damage response activation at stalled replication forks by SPRTN

Nature Communications ◽

10.1038/s41467-019-13610-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Christopher Bruhn ◽

Marco Foiani

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Replication Forks ◽

Damage Response ◽

Stalled Replication Forks ◽

Response Activation

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MOF Suppresses Replication Stress and Contributes to Resolution of Stalled Replication Forks

Molecular and Cellular Biology ◽

10.1128/mcb.00484-17 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 7

Author(s):

Dharmendra Kumar Singh ◽

Raj K. Pandita ◽

Mayank Singh ◽

Sharmistha Chakraborty ◽

Shashank Hambarde ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Replication Stress ◽

Replication Forks ◽

Loop Formation ◽

Origin Firing ◽

Damage Site ◽

Replicative Stress ◽

Damage Response ◽

Stalled Replication Forks

ABSTRACT The human MOF (hMOF) protein belongs to the MYST family of histone acetyltransferases and plays a critical role in transcription and the DNA damage response. MOF is essential for cell proliferation; however, its role during replication and replicative stress is unknown. Here we demonstrate that cells depleted of MOF and under replicative stress induced by cisplatin, hydroxyurea, or camptothecin have reduced survival, a higher frequency of S-phase-specific chromosome damage, and increased R-loop formation. MOF depletion decreased replication fork speed and, when combined with replicative stress, also increased stalled replication forks as well as new origin firing. MOF interacted with PCNA, a key coordinator of replication and repair machinery at replication forks, and affected its ubiquitination and recruitment to the DNA damage site. Depletion of MOF, therefore, compromised the DNA damage repair response as evidenced by decreased Mre11, RPA70, Rad51, and PCNA focus formation, reduced DNA end resection, and decreased CHK1 phosphorylation in cells after exposure to hydroxyurea or cisplatin. These results support the argument that MOF plays an important role in suppressing replication stress induced by genotoxic agents at several stages during the DNA damage response.

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Abstract 1640: Correlations of DNA damage response gene alterations with response to immune checkpoint inhibitors are different in solid tumors

10.1158/1538-7445.am2021-1640 ◽

2021 ◽

Author(s):

Tao Li ◽

Yanling Niu ◽

Tonghui Ma ◽

Danhua Wang ◽

Dong-Dong Jia

Keyword(s):

Dna Damage ◽

Solid Tumors ◽

Dna Damage Response ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Response Gene ◽

Damage Response ◽

Gene Alterations

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APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.738502 ◽

2021 ◽

Vol 9 ◽

Author(s):

Md Akram Hossain ◽

Yunfeng Lin ◽

Garrett Driscoll ◽

Jia Li ◽

Anne McMahon ◽

...

Keyword(s):

Oxidative Stress ◽

Pancreatic Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Dna Damage Response ◽

Human Pancreatic Cancer ◽

Genome Integrity ◽

Pancreatic Cancer Cells ◽

Damage Response ◽

Egg Extracts

The maintenance of genome integrity and fidelity is vital for the proper function and survival of all organisms. Recent studies have revealed that APE2 is required to activate an ATR-Chk1 DNA damage response (DDR) pathway in response to oxidative stress and a defined DNA single-strand break (SSB) in Xenopus laevis egg extracts. However, it remains unclear whether APE2 is a general regulator of the DDR pathway in mammalian cells. Here, we provide evidence using human pancreatic cancer cells that APE2 is essential for ATR DDR pathway activation in response to different stressful conditions including oxidative stress, DNA replication stress, and DNA double-strand breaks. Fluorescence microscopy analysis shows that APE2-knockdown (KD) leads to enhanced γH2AX foci and increased micronuclei formation. In addition, we identified a small molecule compound Celastrol as an APE2 inhibitor that specifically compromises the binding of APE2 but not RPA to ssDNA and 3′-5′ exonuclease activity of APE2 but not APE1. The impairment of ATR-Chk1 DDR pathway by Celastrol in Xenopus egg extracts and human pancreatic cancer cells highlights the physiological significance of Celastrol in the regulation of APE2 functionalities in genome integrity. Notably, cell viability assays demonstrate that APE2-KD or Celastrol sensitizes pancreatic cancer cells to chemotherapy drugs. Overall, we propose APE2 as a general regulator for the DDR pathway in genome integrity maintenance.

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Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

Cancers ◽

10.3390/cancers12082051 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2051 ◽

Cited By ~ 2

Author(s):

Amandine Moretton ◽

Joanna I. Loizou

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Metabolic Regulation ◽

Current Knowledge ◽

Cellular Metabolism ◽

Genome Integrity ◽

Cancer Treatments ◽

Damage Response ◽

Dynamic Interplay ◽

Remarkable Progress

Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.

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