scholarly journals Computational Modeling of Signaling Pathways Mediating Cell Cycle Checkpoint Control and Apoptotic Responses to Ionizing Radiation-Induced DNA Damage

Dose-Response ◽  
2011 ◽  
Vol 10 (2) ◽  
pp. dose-response.1 ◽  
Author(s):  
Yuchao Zhao ◽  
In Chio Lou ◽  
Rory B. Conolly
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Computational Modeling ◽  
Signaling Pathways ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Cycle Checkpoint ◽  
Radiation Induced

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 Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control

1998 ◽  
Vol 95 (13) ◽  
pp. 7445-7450 ◽  
Author(s):  
J. A. Wright ◽  
K. S. Keegan ◽  
D. R. Herendeen ◽  
N. J. Bentley ◽  
A. M. Carr ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Ionizing Radiation ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Cycle Checkpoint

scholarly journals Roles for Basal and Stimulated p21Cip-1/WAF1/MDA6Expression and Mitogen-activated Protein Kinase Signaling in Radiation-induced Cell Cycle Checkpoint Control in Carcinoma Cells

1999 ◽  
Vol 10 (12) ◽  
pp. 4231-4246 ◽  
Author(s):  
Jong-Sung Park ◽  
Steven Carter ◽  
Dean B. Reardon ◽  
Rupert Schmidt-Ullrich ◽  
Paul Dent ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Cell Cycle Checkpoint ◽  
Carcinoma Cells ◽  
Checkpoint Control ◽  
M Phase ◽  
Cycle Checkpoint ◽  
Radiation Induced ◽  
Induced Apoptosis

We investigated the role of the cdk inhibitor protein p21Cip-1/WAF1/MDA6 (p21) in the ability of MAPK pathway inhibition to enhance radiation-induced apoptosis in A431 squamous carcinoma cells. In carcinoma cells, ionizing radiation (2 Gy) caused both primary (0–10 min) and secondary (90–240 min) activations of the MAPK pathway. Radiation induced p21 protein expression in A431 cells within 6 h via secondary activation of the MAPK pathway. Within 6 h, radiation weakly enhanced the proportion of cells in G1 that were p21 and MAPK dependent, whereas the elevation of cells present in G2/M at this time was independent of either p21 expression or MAPK inhibition. Inhibition of the MAPK pathway increased the proportion of irradiated cells in G2/M phase 24–48 h after irradiation and enhanced radiation-induced apoptosis. This correlated with elevated Cdc2 tyrosine 15 phosphorylation, decreased Cdc2 activity, and decreased Cdc25C protein levels. Caffeine treatment or removal of MEK1/2 inhibitors from cells 6 h after irradiation reduced the proportion of cells present in G2/M phase at 24 h and abolished the ability of MAPK inhibition to potentiate radiation-induced apoptosis. These data argue that MAPK signaling plays an important role in the progression/release of cells through G2/M phase after radiation exposure and that an impairment of this progression/release enhances radiation-induced apoptosis. Surprisingly, the ability of irradiation/MAPK inhibition to increase the proportion of cells in G2/M at 24 h was found to be dependent on basal p21 expression. Transient inhibition of basal p21 expression increased the control level of apoptosis as well as the abilities of both radiation and MEK1/2 inhibitors to cause apoptosis. In addition, loss of basal p21 expression significantly reduced the capacity of MAPK inhibition to potentiate radiation-induced apoptosis. Collectively, our data argue that MAPK signaling and p21 can regulate cell cycle checkpoint control in carcinoma cells at the G1/S transition shortly after exposure to radiation. In contrast, inhibition of MAPK increases the proportion of irradiated cells in G2/M, and basal expression of p21 is required to maintain this effect. Our data suggest that basal and radiation-stimulated p21 may play different roles in regulating cell cycle progression that affect cell survival after radiation exposure.

scholarly journals DNA Damage-Induced Cell Cycle Checkpoint Control Requires CtIP, a Phosphorylation-Dependent Binding Partner of BRCA1 C-Terminal Domains

2004 ◽  
Vol 24 (21) ◽  
pp. 9478-9486 ◽  
Author(s):  
Xiaochun Yu ◽  
Junjie Chen
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Molecular Mechanisms ◽  
Cell Cycle Checkpoint ◽  
Dependent Manner ◽  
Checkpoint Control ◽  
Interacting Protein ◽  
Binding Partner ◽  
Cycle Checkpoint ◽  
Multiple Cell

ABSTRACT The BRCA1 C-terminal (BRCT) domain has recently been implicated as a phospho-protein binding domain. We demonstrate here that a CTBP-interacting protein CtIP interacts with BRCA1 BRCT domains in a phosphorylation-dependent manner. The CtIP/BRCA1 complex only exists in G2 phase and is required for DNA damage-induced Chk1 phosphorylation and the G2/M transition checkpoint. However, the CtIP/BRCA1 complex is not required for the damage-induced G2 accumulation checkpoint, which is controlled by a separate BRCA1/BACH1 complex. Taken together, these data not only implicate CtIP as a critical player in cell cycle checkpoint control but also provide molecular mechanisms by which BRCA1 controls multiple cell cycle transitions after DNA damage.

scholarly journals Different DNA damage and cell cycle checkpoint control in low- and high-risk human papillomavirus infections of the vulva

2011 ◽  
Vol 130 (12) ◽  
pp. 2874-2885 ◽  
Author(s):  
Lindy A.M. Santegoets ◽  
Romy van Baars ◽  
Annelinde Terlou ◽  
Claudia Heijmans-Antonissen ◽  
Sigrid M.A. Swagemakers ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Human Papillomavirus ◽  
High Risk ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Papillomavirus Infections ◽  
Cycle Checkpoint

scholarly journals Cell cycle checkpoint control in response to dna damage by environmental stresses

2021 ◽  
Author(s):  
José Antonio Pedroza‐Garcia ◽  
Yanli Xiang ◽  
Lieven De Veylder
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Environmental Stresses ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Cycle Checkpoint

Functionalized graphene oxide triggers cell cycle checkpoint control through both the ATM and the ATR signaling pathways

Carbon ◽  
2018 ◽  
Vol 129 ◽  
pp. 495-503 ◽  
Author(s):  
Yonghui Wang ◽  
Jun Xu ◽  
Ligeng Xu ◽  
Xiaofang Tan ◽  
Liangzhu Feng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Graphene Oxide ◽  
Signaling Pathways ◽  
Cell Cycle Checkpoint ◽  
Functionalized Graphene ◽  
Checkpoint Control ◽  
Functionalized Graphene Oxide ◽  
Cycle Checkpoint

scholarly journals Acetylation of MORC2 by NAT10 regulates cell-cycle checkpoint control and resistance to DNA-damaging chemotherapy and radiotherapy in breast cancer

2020 ◽  
Vol 48 (7) ◽  
pp. 3638-3656 ◽  
Author(s):  
Hong-Yi Liu ◽  
Ying-Ying Liu ◽  
Fan Yang ◽  
Lin Zhang ◽  
Fang-Lin Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Target Genes ◽  
Cyclin B1 ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
G2 Checkpoint ◽  
Cycle Checkpoint

Abstract MORC family CW-type zinc finger 2 (MORC2) is an oncogenic chromatin-remodeling enzyme with an emerging role in DNA repair. Here, we report a novel function for MORC2 in cell-cycle checkpoint control through an acetylation-dependent mechanism. MORC2 is acetylated by the acetyltransferase NAT10 at lysine 767 (K767Ac) and this process is counteracted by the deacetylase SIRT2 under unperturbed conditions. DNA-damaging chemotherapeutic agents and ionizing radiation stimulate MORC2 K767Ac through enhancing the interaction between MORC2 and NAT10. Notably, acetylated MORC2 binds to histone H3 phosphorylation at threonine 11 (H3T11P) and is essential for DNA damage-induced reduction of H3T11P and transcriptional repression of its downstream target genes CDK1 and Cyclin B1, thus contributing to DNA damage-induced G2 checkpoint activation. Chemical inhibition or depletion of NAT10 or expression of an acetylation-defective MORC2 (K767R) forces cells to pass through G2 checkpoint, resulting in hypersensitivity to DNA-damaging agents. Moreover, MORC2 acetylation levels are associated with elevated NAT10 expression in clinical breast tumor samples. Together, these findings uncover a previously unrecognized role for MORC2 in regulating DNA damage-induced G2 checkpoint through NAT10-mediated acetylation and provide a potential therapeutic strategy to sensitize breast cancer cells to DNA-damaging chemotherapy and radiotherapy by targeting NAT10.

scholarly journals Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 750
Author(s):  
Kiyohiro Ando ◽  
Akira Nakagawara
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
Malignant Neoplasms ◽  
Checkpoint Kinases ◽  
Molecular Features ◽  
Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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