Reviews and Advances in our Understanding of the Relationship between the Cell Cycle, DNA Damage and Cancer

Editorial

16 November 2023

Editorial: Reviews and advances in our understanding of the relationship between the cell cycle, DNA damage and cancer

Damien D’Amours

1,602 views

0 citations

Editors

Damien D'Amours

University of Ottawa

Lisa A. Porter

University of Windsor

Daniel Leslie Fisher

Centre National de la Recherche Scientifique (CNRS)

Brian Gabrielli

The University of Queensland

Impact

DNA damage and cell cycle checkpoint inhibitors and their effect on ectopic Cdk1 activation. (A) In an unperturbed cell, Cdk1 and cyclin B bind in late S-phase. Phosphorylation of Cdk1 on T14 and Y15 (depicted with red circles) by Myt1 and Wee1 during interphase inhibits Cdk1/cyclin B. Cdc25 removes these inhibitory phosphorylations and activates the Cdk1/cyclin B complexes allowing cells to enter mitosis. The high level of Wee1 activity in many cancer cells prevents their premature entry into mitosis and facilitates their survival in the presence of elevated genotoxic stress compared to normal cells. (B) Upon addition of Adavosertib (inhibition of Wee1) or PD166285 (inhibition of Wee1 and Myt1), the balance between inactive and active Cdk1/cyclin B1 complexes is shifted leading to more active Cdk1/cyclin B1 complexes. This increases the chance of premature entry into mitosis and cell death. (C) Overexpression of Myt1 in the presence of Adavosertib or PD166285 counters the drugs’ effect because phosphorylation of Cdk1 on T14 and Y15 by Myt1 increases inactive Cdk1/cyclin B complexes. This results in checkpoint arrest and rescue from cell death even in the presence of these cell cycle checkpoint kinase inhibitors. (D) Damaged DNA or replication stress can induce the activation of the DNA damage checkpoint, which downregulates Cdk1/cyclin B activity via Cdc25. ATR activates the effector kinase Chk1, which phosphorylates and inhibits the Cdc25 phosphatase family. In parallel, ATR can induce the stabilization and transcriptional activity of p53 leading to increased expression of the CDK inhibitor p21; however, this pathway is downregulated in many cancers (due to non-functional p53 status of many cancers) (Olivier et al., 2010) . (E) Upon addition of UCN-01 or AZD6738 (inhibition of Chk1 and ATR), Cdc25 inactivation in the presence of DNA damage is repressed and the balance between inactive and active Cdk1/cyclin B1 complexes is shifted towards more active Cdk1/cyclin B1 complexes. The cells are at elevated risk of premature mitotic entry. Restoration of Cdc25 activity in the presence of DNA damage is likely to have a lower effect then inhibiting Wee1 and Myt1 with Adavosertib or PD-166285. (F) Upon overexpression of Myt1 in the presence of UCN-01 or AZD6738 which leads to more inhibitory phosphorylation of Cdk1 on both T14 and Y15, the pool is reverted to more inactive Cdk1/cyclin B1 complexes even in the presence of these DNA damage checkpoint kinase inhibitors. Red arrows are Cdk1 activating pathways whereas black arrows are Cdk1 inactivating pathways. Solid line shows an active pathway, a dotted line an inhibited pathway. The p53 pathway (grey) is abrogated in most cancers. The meter schematically indicates the balance in active/inactive Cdk1 complexes in each scenario and the associated risk of premature entry into mitosis.

Original Research

02 November 2023

Myt1 overexpression mediates resistance to cell cycle and DNA damage checkpoint kinase inhibitors

Sargun Sokhi

, 8 more and

Gordon K. Chan

3,117 views

4 citations

Original Research

12 October 2023

P53 independent pathogenic mechanisms contribute to BubR1 microcephaly

Noelle A. Sterling

, 2 more and

Seonhee Kim

2,605 views

3 citations

The route to replicative senescence. Replicative senescence onset is a multi-step process in which transient cell-cycle arrests occur before the terminal arrest. Transient arrests might be caused by the presence of a repairable damage (e.g., partial telomere uncapping, stochastic DNA damage) or replication stress at telomeres. A weak and confined DDR response might be another possible cause of a transient arrest. Genome instability is likely still low at this point. Cell division arrests might be overcome i) by DNA repair activities (e.g., HDR), eventually leading to telomere elongation, ii) by tolerating a weak DDR response or iii) by switching off the DDR and trying to survive without solving the DNA damage (adaptation). Adaptation clearly leads to increased genome instability, while HDR contribution to genome instability is not clear. The event(s) triggering the terminal senescent arrest might be critically short/irreparable telomere(s), as well as a broader DNA damage. In both cases, an excessive genome instability and/or DDR activation overcoming a certain threshold lead to replicative senescence onset.

Mini Review

13 September 2023

The multistep path to replicative senescence onset: zooming on triggering and inhibitory events at telomeric DNA

Paolo Pizzul

, 1 more and

Diego Bonetti

2,834 views

5 citations

Radiation reduces testicular volume and sperm quality. (A) Experimental design. Testis and epididymis of 8-week-old C57BL mice were collected at 1, 3, and 7 days after whole body radiation exposure. (B) The testis of unirradiated mice and mice exposed to radiation for 7 days. (C) Testicular volume of mice at different time points after radiation exposure. (D) Organ index of testis at different time points after radiation exposure. (E) Sperm morphology. a, normal sperm; b, head unstereotyped sperm; c, tail folding sperm; d, double head deformed sperm. Bar = 50 μm. (F) Sperm quality parameters. From left to right, the sperm morphology, survival rate, concentration, and motility rate were shown. *p < 0.05 vs. CTL. **p < 0.01 vs. CTL. ***p < 0.001 vs. CTL. Dunnett’s multiple comparisons test was used after one-way ANOVA.

Original Research

25 April 2022

Rapamycin Ameliorates Radiation-Induced Testis Damage in Mice

Juan Yang

, 6 more and

Lijian Shao

2,908 views

9 citations

Structural illustration of lamin-A/C. The lamin-A and its isoform C comprise alternative splice variants. NLS, nuclear location signal.

Review

12 May 2023

Overview of cellular homeostasis-associated nuclear envelope lamins and associated input signals

Hyeong Jae Kim

, 1 more and

Jeong Hee Hong

3,661 views

5 citations

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Molecular Networks Controlling Cell Growth and Cell Division Cycle in Cancers

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20 June 2025

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