scholarly journals p53 activates G1 checkpoint following DNA damage by doxorubicin during transient mitotic arrest

Oncotarget ◽  
2014 ◽  
Vol 6 (7) ◽  
pp. 4804-4815 ◽  
Author(s):  
Sun-Yi Hyun ◽  
Young-Joo Jang
Keyword(s):  
Dna Damage ◽  
Mitotic Arrest ◽  
G1 Checkpoint

DNA damage checkpoint kinases in cancer

2020 ◽  
Vol 22 ◽  
Author(s):  
Hannah L. Smith ◽  
Harriet Southgate ◽  
Deborah A. Tweddle ◽  
Nicola J. Curtin
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Environmental Dna ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Integrated Network ◽  
Checkpoint Kinases ◽  
G1 Checkpoint ◽  
Cycle Checkpoint ◽  
High Level

Abstract DNA damage response (DDR) pathway prevents high level endogenous and environmental DNA damage being replicated and passed on to the next generation of cells via an orchestrated and integrated network of cell cycle checkpoint signalling and DNA repair pathways. Depending on the type of damage, and where in the cell cycle it occurs different pathways are involved, with the ATM-CHK2-p53 pathway controlling the G1 checkpoint or ATR-CHK1-Wee1 pathway controlling the S and G2/M checkpoints. Loss of G1 checkpoint control is common in cancer through TP53, ATM mutations, Rb loss or cyclin E overexpression, providing a stronger rationale for targeting the S/G2 checkpoints. This review will focus on the ATM-CHK2-p53-p21 pathway and the ATR-CHK1-WEE1 pathway and ongoing efforts to target these pathways for patient benefit.

scholarly journals AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma

2020 ◽  
Vol 27 (7) ◽  
pp. 2081-2098 ◽  
Author(s):  
Ishani Das ◽  
Helge Gad ◽  
Lars Bräutigam ◽  
Linda Pudelko ◽  
Rainer Tuominen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Cell Death ◽  
Malignant Melanoma ◽  
Braf Inhibitor ◽  
Mitotic Arrest ◽  
Cutaneous Malignant Melanoma ◽  
Clinical Samples

AbstractCutaneous malignant melanoma (CMM) is the deadliest form of skin cancer and clinically challenging due to its propensity to develop therapy resistance. Reactive oxygen species (ROS) can induce DNA damage and play a significant role in CMM. MTH1 protein protects from ROS damage and is often overexpressed in different cancer types including CMM. Herein, we report that MTH1 inhibitor TH1579 induced ROS levels, increased DNA damage responses, caused mitotic arrest and suppressed CMM proliferation leading to cell death both in vitro and in an in vivo xenograft CMM zebrafish disease model. TH1579 was more potent in abrogating cell proliferation and inducing cell death in a heterogeneous co-culture setting when compared with CMM standard treatments, vemurafenib or trametinib, showing its broad anticancer activity. Silencing MTH1 alone exhibited similar cytotoxic effects with concomitant induction of mitotic arrest and ROS induction culminating in cell death in most CMM cell lines tested, further emphasizing the importance of MTH1 in CMM cells. Furthermore, overexpression of receptor tyrosine kinase AXL, previously demonstrated to contribute to BRAF inhibitor resistance, sensitized BRAF mutant and BRAF/NRAS wildtype CMM cells to TH1579. AXL overexpression culminated in increased ROS levels in CMM cells. Moreover, silencing of a protein that has shown opposing effects on cell proliferation, CAV-1, decreased sensitivity to TH1579 in a BRAF inhibitor resistant cell line. AXL-MTH1 and CAV-1-MTH1 mRNA expressions were correlated as seen in CMM clinical samples. Finally, TH1579 in combination with BRAF inhibitor exhibited a more potent cell killing effect in BRAF mutant cells both in vitro and in vivo. In summary, we show that TH1579-mediated efficacy is independent of BRAF/NRAS mutational status but dependent on the expression of AXL and CAV-1.

scholarly journals Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Iraia García-Santisteban ◽  
Alba Llopis ◽  
Lenno Krenning ◽  
Jon Vallejo-Rodríguez ◽  
Bram van den Broek ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Cycle Progression ◽  
Double Strand Breaks ◽  
G1 Arrest ◽  
Dna Double Strand Breaks ◽  
Independent Manner ◽  
Cycle Progression ◽  
Strand Breaks ◽  
G1 Checkpoint ◽  
The Impact

Abstract Background The G1 checkpoint is a critical regulator of genomic stability in untransformed cells, preventing cell cycle progression after DNA damage. DNA double-strand breaks (DSBs) recruit and activate ATM, a kinase which in turn activates the CHK2 kinase to establish G1 arrest. While the onset of G1 arrest is well understood, the specific role that ATM and CHK2 play in regulating G1 checkpoint maintenance remains poorly characterized. Results Here we examine the impact of ATM and CHK2 activities on G1 checkpoint maintenance in untransformed cells after DNA damage caused by DSBs. We show that ATM becomes dispensable for G1 checkpoint maintenance as early as 1 h after DSB induction. In contrast, CHK2 kinase activity is necessary to maintain the G1 arrest, independently of ATM, ATR, and DNA-PKcs, implying that the G1 arrest is maintained in a lesion-independent manner. Sustained CHK2 activity is achieved through auto-activation and its acute inhibition enables cells to abrogate the G1-checkpoint and enter into S-phase. Accordingly, we show that CHK2 activity is lost in cells that recover from the G1 arrest, pointing to the involvement of a phosphatase with fast turnover. Conclusion Our data indicate that G1 checkpoint maintenance relies on CHK2 and that its negative regulation is crucial for G1 checkpoint recovery after DSB induction.

scholarly journals Prolonged mitotic arrest induces a caspase-dependent DNA damage response at telomeres that determines cell survival

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Karolina O. Hain ◽  
Didier J. Colin ◽  
Shubhra Rastogi ◽  
Lindsey A. Allan ◽  
Paul R. Clarke
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Dna Damage Response ◽  
Mitotic Arrest ◽  
Damage Response

scholarly journals DNA damage induces downregulation of histone gene expression through the G1 checkpoint pathway

2004 ◽  
Vol 23 (5) ◽  
pp. 1133-1143 ◽  
Author(s):  
Chuan Su ◽  
Guang Gao ◽  
Sandra Schneider ◽  
Christopher Helt ◽  
Carsten Weiss ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Histone Gene ◽  
Histone Gene Expression ◽  
Checkpoint Pathway ◽  
G1 Checkpoint

scholarly journals PP2A-Cdc55 is responsible for mitotic arrest in DNA re-replicating cells in S. cerevisiae

2020 ◽  
Author(s):  
Shoily Khondker ◽  
Amy E. Ikui
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Arrest ◽  
Cell Cycle Checkpoints ◽  
Genome Integrity ◽  
Cyclin Dependent Kinase ◽  
Metaphase Arrest ◽  
Daughter Cells ◽  
Origin Licensing

AbstractThe cell cycle is an ordered process in which cells replicate their DNA in S-phase and divide them into two identical daughter cells in mitosis. DNA replication takes place only once per cell cycle to preserve genome integrity, which is tightly regulated by Cyclin Dependent Kinase (CDK). Formation of the pre-replicative complex, a platform for origin licensing, is inhibited through CDK-dependent phosphorylation. Failure of this control leads to re-licensing, re-replication and DNA damage. Eukaryotic cells have evolved surveillance mechanisms to maintain genome integrity, termed cell cycle checkpoints. It has been shown that the DNA damage checkpoint is activated upon the induction of DNA re-replication and arrests cell cycle in mitosis in S. cerevisiae. In this study, we show that PP2A-Cdc55 is responsible for the metaphase arrest induced by DNA re-replication, leading to dephosphorylation of APC component, Exclusion of Cdc55 from the nucleus bypassed the mitotic arrest and resulted in enhanced cell lethality in re-replicating cells. The metaphase arrest in re-replication cells was retained in the absence of Mad2, a key component of the spindle assembly checkpoint. Moreover, re-replicating cells showed the same rate of DNA damage induction in the presence or absence of Cdc55. These results indicate that PP2A-Cdc55 maintains metaphase arrest upon DNA re-replication and DNA damage through APC inhibition.

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