ArticleOncogene2015
DNA-PK/Chk2 induces centrosome amplification during prolonged replication stress.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
- Indium (III) chloride inhibits testicular Leydig cell proliferation by disrupting centrosome copy numbers.Molecular medicine reports · 2026Article
- Checkpoint kinase 2 coordinates autophagy activation and Aurora kinase A degradation to regulate primary cilia for cell invasion.Cell communication and signaling : CCS · 2026Article
- Unlocking the Therapeutic Potential of DNA-PKcs in Cancer: Comprehensive Insights into Mechanisms and Clinical Applications.Cancers · 2025Review
- Targeting the DNA damage response in hematological malignancies.Frontiers in oncology · 2024Review
- Polo‑like kinase 1 selective inhibitor BI2536 (dihydropteridinone) disrupts centrosome homeostasis via ATM‑ERK cascade in adrenocortical carcinoma.Oncology reports · 2023Article
- The fate of extra centrosomes in newly formed tetraploid cells: should I stay, or should I go?Frontiers in cell and developmental biology · 2023Review
- CHK2 activation contributes to the development of oxaliplatin resistance in colorectal cancer.British journal of cancer · 2022Article
- Role of DNA-Dependent Protein Kinase in Mediating Cyst Growth in Autosomal Dominant Polycystic Kidney Disease.International journal of molecular sciences · 2021Article
- Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting.World journal of stem cells · 2021Review
- Article
- Dysregulation of the centrosome induced by BRCA1 deficiency contributes to tissue-specific carcinogenesis.Cancer science · 2021Review
- Xeroderma Pigmentosum: A Model for Human Premature Aging.The Journal of investigative dermatology · 2021Review
- Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy.Biomedicines · 2021Review
- DNA damage promotes microtubule dynamics through a DNA-PK-AKT axis for enhanced repair.The Journal of cell biology · 2021Article
- Review
- DNA-PKcs: A Multi-Faceted Player in DNA Damage Response.Frontiers in genetics · 2020Review
- Cordycepin Inhibits Human Gestational Choriocarcinoma Cell Growth by Disrupting Centrosome Homeostasis.Drug design, development and therapy · 2020Article
- Chk2-dependent phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) regulates centrosome maturation.Cell cycle (Georgetown, Tex.) · 2019Article
- Clinically Applicable Inhibitors Impacting Genome Stability.Molecules (Basel, Switzerland) · 2018Review
- BMI1 reduces ATR activation and signalling caused by hydroxyurea.Oncotarget · 2017Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The antineoplastic drug hydroxyurea (HU), when used at subtoxic doses, induces prolonged replication stress and centrosome amplification. This causes genomic instability and increases the malignancy of the recurring tumor. The mechanism of centrosome amplification induced by prolonged replication stress, however, is still unclear. Here, we examined the involvement of ataxia telangiectasia, mutated (ATM), ataxia telangiectasia, mutated and Rad3-related (ATR) and DNA-dependent protein kinase (DNA-PK) and found that HU-induced centrosome amplification was inhibited by the depletion of DNA-PKcs, but not ATM and ATR. Inactivation of ATM/ATR in U2OS cells instead caused aneuploidy and cell death. We found DNA-PKcs depletion also abrogated ATM phosphorylation, indicating that ATM activation during prolonged replication stress depends on DNA-PK. Depletion of DNA-PK abrogated checkpoint kinase (Chk)2 activation and partially reduced Chk1 activation. Chk2 depletion blocked HU-induced centrosome amplification, indicating a function of Chk2 in centrosome amplification. We further found that Chk2 was phosphorylated at Thr68 on the mother centriole at late G2 and mitosis when unstressed and on all amplified centrioles induced by HU. In summary, we have elucidated that DNA-PK/Chk2 signaling induces centrosome amplification upon long-term HU treatment, therefore increasing our insight into tumor recurrence after initial chemotherapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.