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

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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Chemical strategies for development of ATR inhibitors

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2014.10 ◽

2014 ◽

Vol 16 ◽

Cited By ~ 15

Author(s):

Sabin Llona-Minguez ◽

Andreas Höglund ◽

Sylvain A. Jacques ◽

Tobias Koolmeister ◽

Thomas Helleday

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Checkpoint Inhibitors ◽

Genome Integrity ◽

Signalling Pathways ◽

Replication Forks ◽

Damage Response ◽

Key Players ◽

Chemical Strategies ◽

Stalled Replication Forks

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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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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Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

Oncogene ◽

10.1038/sj.onc.1210974 ◽

2007 ◽

Vol 27 (22) ◽

pp. 3186-3193 ◽

Cited By ~ 8

Author(s):

M S Frech ◽

K M Torre ◽

G W Robinson ◽

P A Furth

Keyword(s):

Dna Damage ◽

Estrogen Receptor ◽

Mammary Gland ◽

Cyclin D1 ◽

Dna Damage Response ◽

Estrogen Receptor Α ◽

Damage Response ◽

Mammary Gland Morphogenesis ◽

Gland Morphogenesis ◽

Response Activation

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Faculty Opinions recommendation of ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734831207.793557672 ◽

2019 ◽

Author(s):

Susan Lees-Miller

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Replication Forks ◽

End Joining ◽

Damage Response ◽

Non Homologous End Joining

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Faculty Opinions recommendation of ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734831207.793557450 ◽

2019 ◽

Author(s):

Antony Carr

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Replication Forks ◽

End Joining ◽

Damage Response ◽

Non Homologous End Joining

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Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

10.1101/621623 ◽

2019 ◽

Cited By ~ 2

Author(s):

Elaine Sanij ◽

Katherine M. Hannan ◽

Shunfei Yan ◽

Jiachen Xuan ◽

Jessica E. Ahern ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Parp Inhibitors ◽

Rna Polymerase I ◽

High Grade ◽

Replication Forks ◽

Serous Ovarian Cancer ◽

Damage Response ◽

Polymerase I

AbstractHigh-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX)in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

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