p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways

Roy, Sunetra; Tomaszowski, Karl Heinz; Luzwick, Jessica W.; Park, Soyoung; Li, Jun; Murphy, Maureen E.; Schlacher, Katharina

doi:10.7554/elife.31723

Cited by 76 publications

(84 citation statements)

References 74 publications

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“…Resistance to AZD1775-induced replication stress at a replication fork level likely involves a RAD18-TLS polymerase kappa-dependent tolerance pathway and a RAD51-dependent fork protection pathway (13). We propose that p53 may regulate a choice between these pathways both directly (42,43) and in a transcriptionmediated manner (44).…”

Section: Discussionmentioning

confidence: 92%

“…This novel observation can imply that on a cell-by-cell basis, gH2AX response to replication stress is actually dampened by the knockdown of p53, and/or that p53 facilitates fork progression under stress. A stimulatory role of p53 in stressed fork progression was found by some studies (41,42) but not others (43). Resistance to AZD1775-induced replication stress at a replication fork level likely involves a RAD18-TLS polymerase kappa-dependent tolerance pathway and a RAD51-dependent fork protection pathway (13).…”

Section: Discussionmentioning

confidence: 96%

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Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Diab

Kao

Kehrli

et al. 2019

Molecular Cancer Research

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The p53 gene is the most commonly mutated gene in solid tumors, but leveraging p53 status in therapy remains a challenge. Previously, we determined that p53 deficiency sensitizes head and neck cancer cells to AZD1775, a WEE1 kinase inhibitor, and translated our findings into a phase I clinical trial. Here, we investigate how p53 affects cellular responses to AZD1775 at the molecular level. We found that p53 modulates both replication stress and mitotic deregulation triggered by WEE1 inhibition. Without p53, slowing of replication forks due to replication stress is exacerbated. Abnormal, gH2AX-positive mitoses become more common and can proceed with damaged or underreplicated DNA. p53-deficient cells fail to properly recover from WEE1 inhibition and exhibit fewer 53BP1 nuclear bodies despite evidence of unresolved damage. A faulty G 1 -S checkpoint propagates this damage into the next division. Together, these deficiencies can intensify damages in each consecutive cell cycle in the drug. Implications:The data encourage the use of AZD1775 in combination with genotoxic modalities against p53-deficient head and neck squamous cell carcinoma. Results Cell-cycle progression and DNA-damage/replication stress response in WEE1 inhibitor-treated HNSCC cellsPhenotypes elicited by a therapeutically relevant dose of the WEE1 inhibitor AZD1775 were first demonstrated in the TP53 Diab et al.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Diab

Kao

Kehrli

et al. 2019

Molecular Cancer Research

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“…Thus, it is tempting to speculate that functional p53 provides resistance to deformation-induced replication stress and DNA damage. Consistent with this idea, p53 can mediate replication stress and restart DNA replication at stalled forks, thereby preventing replication fork collapse and associated DNA damage (Roy et al, 2018). At the same time, differences in the susceptibility of cells to NE rupture-induced DNA damage could be due to differences in the expression of cytoplasmic nucleases (Nader et al, 2020;Hatch, 2018) or other factors.…”

Section: Discussionmentioning

confidence: 92%

Nuclear deformation causes DNA damage by increasing replication stress

Shah

Cheng

Hobson

et al. 2020

Preprint

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Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA damage. The molecular mechanisms responsible for the confined migrationinduced DNA damage remain incompletely understood. While in some cell lines, DNA damage is closely associated with nuclear envelope rupture, we show that in others, mechanical deformation of the nucleus is sufficient to cause DNA damage, even in the absence of nuclear envelope rupture. This deformation-induced DNA damage, unlike nuclear envelope ruptureinduced DNA damage, occurs primarily in S/G2 phase of the cell cycle and is associated with stalled replication forks. Nuclear deformation, resulting from either confined migration or external cell compression, increases replication fork stalling and replication stress, providing a molecular mechanism for the deformation-induced DNA damage. Thus, we have uncovered a new mechanism for mechanically induced DNA damage, linking mechanical deformation of the nucleus to DNA replication stress. This mechanically induced DNA damage could not only increase genomic instability in metastasizing cancer cells, but could also cause DNA damage in nonmigrating cells and tissues that experience mechanical compression during development, thereby contributing to tumorigenesis and DNA damage response activation.

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“…This unraveled resistance mechanism underscores the critical role for MRE11 in the regulated and error-free fork restart and how loss of MRE11 or its regulation at forks can rebalance damage responses in cancer cells. In fact, this may be the basis for genome instability from p53 mutations (159). …”

Section: Mrn and Replication Fork Dynamicsmentioning

confidence: 99%

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Syed

Tainer

2018

Annu. Rev. Biochem.

326

345

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Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette–ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11–RAD50–NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. MRN can interfere with cancer therapy and is an attractive target for precision medicine. Its conformations change the paradigm whereby kinases initiate damage sensing. Delineated results reveal kinase activation, posttranslational targeting, functional scaffolding, conformations storing binding energy and en-abling access, interactions with hub proteins such as replication protein A (RPA), and distinct networks at DNA breaks and forks. MRN biochemistry provides prototypic insights into how it initiates, implements, and regulates multifunctional responses to genomic stress.

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p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways

Cited by 76 publications

References 74 publications

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Nuclear deformation causes DNA damage by increasing replication stress

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

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