scholarly journals Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kathleen Ho ◽  
Hongwei Luo ◽  
Wei Zhu ◽  
Yi Tang
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Genotoxic Stress ◽  
Dna Damage Checkpoint ◽  
Cycle Progression ◽  
Essential Step

AbstractCHK1 is a crucial DNA damage checkpoint kinase and its activation, which requires ATR and RAD17, leads to inhibition of DNA replication and cell cycle progression. Recently, we reported that SMG7 stabilizes and activates p53 to induce G1 arrest upon DNA damage; here we show that SMG7 plays a critical role in the activation of the ATR-CHK1 axis. Following genotoxic stress, SMG7-null cells exhibit deficient ATR signaling, indicated by the attenuated phosphorylation of CHK1 and RPA32, and importantly, unhindered DNA replication and fork progression. Through its 14-3-3 domain, SMG7 interacts directly with the Ser635-phosphorylated RAD17 and promotes chromatin retention of the 9-1-1 complex by the RAD17-RFC, an essential step to CHK1 activation. Furthermore, through maintenance of CHK1 activity, SMG7 controls G2-M transition and facilitates orderly cell cycle progression during recovery from replication stress. Taken together, our data reveals SMG7 as an indispensable signaling component in the ATR-CHK1 pathway during genotoxic stress response.

scholarly journals Regulation of Cell Division in Bacteria by Monitoring Genome Integrity and DNA Replication Status

2019 ◽  
Vol 202 (2) ◽  
Author(s):  
Peter E. Burby ◽  
Lyle A. Simmons
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Sos Response ◽  
Bacterial Cells ◽  
Cycle Progression ◽  
Content Type

ABSTRACT All organisms regulate cell cycle progression by coordinating cell division with DNA replication status. In eukaryotes, DNA damage or problems with replication fork progression induce the DNA damage response (DDR), causing cyclin-dependent kinases to remain active, preventing further cell cycle progression until replication and repair are complete. In bacteria, cell division is coordinated with chromosome segregation, preventing cell division ring formation over the nucleoid in a process termed nucleoid occlusion. In addition to nucleoid occlusion, bacteria induce the SOS response after replication forks encounter DNA damage or impediments that slow or block their progression. During SOS induction, Escherichia coli expresses a cytoplasmic protein, SulA, that inhibits cell division by directly binding FtsZ. After the SOS response is turned off, SulA is degraded by Lon protease, allowing for cell division to resume. Recently, it has become clear that SulA is restricted to bacteria closely related to E. coli and that most bacteria enforce the DNA damage checkpoint by expressing a small integral membrane protein. Resumption of cell division is then mediated by membrane-bound proteases that cleave the cell division inhibitor. Further, many bacterial cells have mechanisms to inhibit cell division that are regulated independently from the canonical LexA-mediated SOS response. In this review, we discuss several pathways used by bacteria to prevent cell division from occurring when genome instability is detected or before the chromosome has been fully replicated and segregated.

scholarly journals A Critical Role of TET1/2 Proteins in Cell-Cycle Progression of Trophoblast Stem Cells

2018 ◽  
Vol 10 (4) ◽  
pp. 1355-1368 ◽  
Author(s):  
Stephanie Chrysanthou ◽  
Claire E. Senner ◽  
Laura Woods ◽  
Elena Fineberg ◽  
Hanneke Okkenhaug ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cycle Progression ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

scholarly journals DNA damage checkpoint dynamics drive cell cycle phase transitions

2017 ◽  
Author(s):  
Hui Xiao Chao ◽  
Cere E. Poovey ◽  
Ashley A. Privette ◽  
Gavin D. Grant ◽  
Hui Yan Chao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Phase Transitions ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Dna Damage Checkpoint ◽  
Cycle Progression ◽  
Dna Damage Checkpoints

ABSTRACTDNA damage checkpoints are cellular mechanisms that protect the integrity of the genome during cell cycle progression. In response to genotoxic stress, these checkpoints halt cell cycle progression until the damage is repaired, allowing cells enough time to recover from damage before resuming normal proliferation. Here, we investigate the temporal dynamics of DNA damage checkpoints in individual proliferating cells by observing cell cycle phase transitions following acute DNA damage. We find that in gap phases (G1 and G2), DNA damage triggers an abrupt halt to cell cycle progression in which the duration of arrest correlates with the severity of damage. However, cells that have already progressed beyond a proposed “commitment point” within a given cell cycle phase readily transition to the next phase, revealing a relaxation of checkpoint stringency during later stages of certain cell cycle phases. In contrast to G1 and G2, cell cycle progression in S phase is significantly less sensitive to DNA damage. Instead of exhibiting a complete halt, we find that increasing DNA damage doses leads to decreased rates of S-phase progression followed by arrest in the subsequent G2. Moreover, these phase-specific differences in DNA damage checkpoint dynamics are associated with corresponding differences in the proportions of irreversibly arrested cells. Thus, the precise timing of DNA damage determines the sensitivity, rate of cell cycle progression, and functional outcomes for damaged cells. These findings should inform our understanding of cell fate decisions after treatment with common cancer therapeutics such as genotoxins or spindle poisons, which often target cells in a specific cell cycle phase.

scholarly journals Cdc25A Serine 123 Phosphorylation Couples Centrosome Duplication with DNA Replication and Regulates Tumorigenesis

2008 ◽  
Vol 28 (24) ◽  
pp. 7442-7450 ◽  
Author(s):  
Sathyavageeswaran Shreeram ◽  
Weng Kee Hee ◽  
Dmitry V. Bulavin
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Phosphorylation Site ◽  
Centrosome Duplication ◽  
Cycle Progression ◽  
Cdc25a Phosphatase

ABSTRACT The cell division cycle 25A (Cdc25A) phosphatase is a critical regulator of cell cycle progression under normal conditions and after stress. Stress-induced degradation of Cdc25A has been proposed as a major way of delaying cell cycle progression. In vitro studies pointed toward serine 123 as a key site in regulation of Cdc25A stability after exposure to ionizing radiation (IR). To address the role of this phosphorylation site in vivo, we generated a knock-in mouse in which alanine was substituted for serine 123. The Cdc25 S123A knock-in mice appeared normal, and, unexpectedly, cells derived from them exhibited unperturbed cell cycle and DNA damage responses. In turn, we found that Cdc25A was present in centrosomes and that Cdc25A levels were not reduced after IR in knock-in cells. This resulted in centrosome amplification due to lack of induction of Cdk2 inhibitory phosphorylation after IR specifically in centrosomes. Further, Cdc25A knock-in animals appeared sensitive to IR-induced carcinogenesis. Our findings indicate that Cdc25A S123 phosphorylation is crucial for coupling centrosome duplication to DNA replication cycles after DNA damage and therefore is likely to play a role in the regulation of tumorigenesis.

The critical role of cyclin D2 in cell cycle progression and tumorigenicity of glioblastoma stem cells

Oncogene ◽  
2012 ◽  
Vol 32 (33) ◽  
pp. 3840-3845 ◽  
Author(s):  
R Koyama-Nasu ◽  
Y Nasu-Nishimura ◽  
T Todo ◽  
Y Ino ◽  
N Saito ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cyclin D2 ◽  
Cycle Progression ◽  
Glioblastoma Stem Cells

scholarly journals The DNA Damage-Induced Cell Cycle Checkpoints

2000 ◽  
Vol 2 (4) ◽  
pp. 237-243
Author(s):  
Piotr Widlak
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Critical Role ◽  
Cell Cycle Checkpoints ◽  
Signal Transduction Pathways ◽  
Cycle Progression

The proliferation of eukaryotic cells is driven by a process called the cell cycle. Proper regulation of this process, leading to orderly execution of sequential steps within the cycle, ensures normal development and homeostasis of the organism. On the other hand, perturbations of the cell cycle are frequently attributed to cancer cells. Mechanisms that ensure the order and fidelity of events in the cell cycle are called checkpoints. The checkpoints induced by damaged DNA delay the cell cycle progression, providing more time for repair of lesion before DNA replication and segregation. The DNA damage-induced checkpoints can be recognized as signal transduction pathways that communicate information between DNA lesion and components of the cell cycle. Proteins involved in the cell cycle, as well as components of the signal transduction pathways communicating with the cell cycle, are frequently products of oncogenes and tumor suppressor genes. Malfunction of these genes plays a critical role in the development of human cancers. The key component in the checkpoint machinery is tumor suppressor gene p53, involved in either regulation of the cell cycle progression (e.g. Gl arrest of cells treated with DNA damaging factor) or activation of programmed cell death (apoptosis). It is postulated that p53 protein is activated by DNA damage detectors. One of the candidates for this role is DNA-dependent protein kinase (DNA-PK) which recognizes DNA strand breaks and phosphorylates p53 protein.

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