BRCA1 Activates a G2-M Cell Cycle Checkpoint following 6-Thioguanine–Induced DNA Mismatch Damage

ABSTRACT Epstein-Barr virus (EBV) infects most of the human population and persists in B lymphocytes for the lifetime of the host. The establishment of latent infection by EBV requires the expression of a unique repertoire of genes. The product of one of these viral genes, the EBV nuclear antigen 3C (EBNA3C), is essential for the growth transformation of primary B lymphocytes in vitro and can regulate the transcription of a number of viral and cellular genes important for the immortalization process. This study demonstrates an associated function of EBNA3C which involves the disruption of the G2/M cell cycle checkpoint. We show that EBNA3C-expressing lymphoblastoid cell lines treated with the drug nocodazole, which is known to block cells at the G2/M transition, did not show a G2/M-specific checkpoint arrest. Analyses of the cell cycles of cells expressing EBNA3C demonstrated that the expression of this essential EBV nuclear antigen is capable of releasing the G2/M checkpoint arrest induced by nocodazole. This G2/M arrest in response to nocodazole was also abolished by caffeine, suggesting an involvement of the ATM/ATR signaling pathway in the regulation of this cell cycle checkpoint. Importantly, we show that the direct interaction of EBNA3C with Chk2, the ATM/ATR signaling effector, is responsible for the release of this nocodazole-induced G2/M arrest and that this interaction leads to the serine 216 phosphorylation of Cdc25c, which is sequestered in the cytoplasm by 14-3-3. Overall, our data suggest that EBNA3C can directly regulate the G2/M component of the host cell cycle machinery, allowing for the release of the checkpoint block.

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Sp1 contributes to radioresistance of cervical cancer through targeting G2/M cell cycle checkpoint CDK1

Cancer Management and Research ◽

10.2147/cmar.s200907 ◽

2019 ◽

Vol Volume 11 ◽

pp. 5835-5844 ◽

Cited By ~ 8

Author(s):

Yuan-Run Deng ◽

Xiao-Jing Chen ◽

Wei Chen ◽

Lan-Fang Wu ◽

Hui-Ping Jiang ◽

...

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cell Cycle Checkpoint ◽

M Cell ◽

Cycle Checkpoint

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The Nuclear Death Domain Protein p84N5 Activates a G2/M Cell Cycle Checkpoint Prior to the Onset of Apoptosis

Journal of Biological Chemistry ◽

10.1074/jbc.m006944200 ◽

2000 ◽

Vol 276 (2) ◽

pp. 1127-1132 ◽

Cited By ~ 9

Author(s):

Jaleh Doostzadeh-Cizeron ◽

Nicholas H. A. Terry ◽

David W. Goodrich

Keyword(s):

Cell Cycle ◽

Cell Cycle Checkpoint ◽

Death Domain ◽

M Cell ◽

Cycle Checkpoint ◽

Domain Protein

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Activation of p38 MAP kinase by DNA double-strand breaks in V(D)J recombination induces a G2/M cell cycle checkpoint

The EMBO Journal ◽

10.1038/sj.emboj.7600972 ◽

2006 ◽

Vol 25 (4) ◽

pp. 763-773 ◽

Cited By ~ 46

Author(s):

Gustavo Pedraza-Alva ◽

Miroslav Koulnis ◽

Colette Charland ◽

Tina Thornton ◽

James L Clements ◽

...

Keyword(s):

Cell Cycle ◽

Map Kinase ◽

P38 Map Kinase ◽

Cell Cycle Checkpoint ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

M Cell ◽

Strand Breaks ◽

Cycle Checkpoint

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17-Allylamino-17-Demethoxygeldanamycin (17-AAG) abrogates the G2/M cell cycle checkpoint by down-regulating chk1 and selectively sensitizes tumor cells with defective p53 to topoisomerase I poison

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.3069 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 3069-3069 ◽

Cited By ~ 1

Author(s):

A. N. Tse ◽

D. Solit ◽

N. Rosen ◽

G. Schwartz

Keyword(s):

Cell Cycle ◽

Tumor Cells ◽

Topoisomerase I ◽

Cell Cycle Checkpoint ◽

M Cell ◽

Cycle Checkpoint

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Activation of Akt/Protein Kinase B Overcomes a G2/M Cell Cycle Checkpoint Induced by DNA Damage

Molecular and Cellular Biology ◽

10.1128/mcb.22.22.7831-7841.2002 ◽

2002 ◽

Vol 22 (22) ◽

pp. 7831-7841 ◽

Cited By ~ 190

Author(s):

Eugene S. Kandel ◽

Jennifer Skeen ◽

Nathan Majewski ◽

Antonio Di Cristofano ◽

Pier Paolo Pandolfi ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Protein Kinase ◽

Protein Kinase B ◽

Es Cells ◽

Cell Cycle Checkpoint ◽

Wild Type ◽

M Cell ◽

Human Cancers ◽

Cycle Checkpoint

ABSTRACT Activation of Akt, or protein kinase B, is frequently observed in human cancers. Here we report that Akt activation via overexpression of a constitutively active form or via the loss of PTEN can overcome a G2/M cell cycle checkpoint that is induced by DNA damage. Activated Akt also alleviates the reduction in CDC2 activity and mitotic index upon exposure to DNA damage. In addition, we found that PTEN null embryonic stem (ES) cells transit faster from the G2/M to the G1 phase of the cell cycle when compared to wild-type ES cells and that inhibition of phosphoinositol-3-kinase (PI3K) in HEK293 cells elicits G2 arrest that is alleviated by activated Akt. Furthermore, the transition from the G2/M to the G1 phase of the cell cycle in Akt1 null mouse embryo fibroblasts (MEFs) is attenuated when compared to that of wild-type MEFs. These results indicate that the PI3K/PTEN/Akt pathway plays a role in the regulation of G2/M transition. Thus, cells expressing activated Akt continue to divide, without being eliminated by apoptosis, in the presence of continuous exposure to mutagen and accumulate mutations, as measured by inactivation of an exogenously expressed herpes simplex virus thymidine kinase (HSV-tk) gene. This phenotype is independent of p53 status and cannot be reproduced by overexpression of Bcl-2 or Myc and Bcl-2 but seems to counteract a cell cycle checkpoint mediated by DNA mismatch repair (MMR). Accordingly, restoration of the G2/M cell cycle checkpoint and apoptosis in MMR-deficient cells, through reintroduction of the missing component of MMR, is alleviated by activated Akt. We suggest that this new activity of Akt in conjunction with its antiapoptotic activity may contribute to genetic instability and could explain its frequent activation in human cancers.

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IKKα Shields 14-3-3σ, a G2/M Cell Cycle Checkpoint Gene, from Hypermethylation, Preventing Its Silencing

Molecular Cell ◽

10.1016/j.molcel.2007.05.042 ◽

2007 ◽

Vol 27 (2) ◽

pp. 214-227 ◽

Cited By ~ 41

Author(s):

Feng Zhu ◽

Xiaojun Xia ◽

Bigang Liu ◽

Jianjun Shen ◽

Yuhui Hu ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Checkpoint ◽

M Cell ◽

Checkpoint Gene ◽

Cycle Checkpoint

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Exploring the ATR-CHK1 pathway in the response of doxorubicin-induced DNA damages in acute lymphoblastic leukemia cells

Cell Biology and Toxicology ◽

10.1007/s10565-021-09640-x ◽

2021 ◽

Author(s):

Andrea Ghelli Luserna Di Rorà ◽

Martina Ghetti ◽

Lorenzo Ledda ◽

Anna Ferrari ◽

Matteo Bocconcelli ◽

...

Keyword(s):

Cell Cycle ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Cell Lines ◽

Lymphoblastic Leukemia ◽

Cell Cycle Checkpoint ◽

M Cell ◽

Dna Damages ◽

Cycle Checkpoint ◽

Dna Double Helix

AbstractDoxorubicin (Dox) is one of the most commonly used anthracyclines for the treatment of solid and hematological tumors such as B−/T cell acute lymphoblastic leukemia (ALL). Dox compromises topoisomerase II enzyme functionality, thus inducing structural damages during DNA replication and causes direct damages intercalating into DNA double helix. Eukaryotic cells respond to DNA damages by activating the ATM-CHK2 and/or ATR-CHK1 pathway, whose function is to regulate cell cycle progression, to promote damage repair, and to control apoptosis. We evaluated the efficacy of a new drug schedule combining Dox and specific ATR (VE-821) or CHK1 (prexasertib, PX) inhibitors in the treatment of human B−/T cell precursor ALL cell lines and primary ALL leukemic cells. We found that ALL cell lines respond to Dox activating the G2/M cell cycle checkpoint. Exposure of Dox-pretreated ALL cell lines to VE-821 or PX enhanced Dox cytotoxic effect. This phenomenon was associated with the abrogation of the G2/M cell cycle checkpoint with changes in the expression pCDK1 and cyclin B1, and cell entry in mitosis, followed by the induction of apoptosis. Indeed, the inhibition of the G2/M checkpoint led to a significant increment of normal and aberrant mitotic cells, including those showing tripolar spindles, metaphases with lagging chromosomes, and massive chromosomes fragmentation. In conclusion, we found that the ATR-CHK1 pathway is involved in the response to Dox-induced DNA damages and we demonstrated that our new in vitro drug schedule that combines Dox followed by ATR/CHK1 inhibitors can increase Dox cytotoxicity against ALL cells, while using lower drug doses. Graphical abstract • Doxorubicin activates the G2/M cell cycle checkpoint in acute lymphoblastic leukemia (ALL) cells. • ALL cells respond to doxorubicin-induced DNA damages by activating the ATR-CHK1 pathway. • The inhibition of the ATR-CHK1 pathway synergizes with doxorubicin in the induction of cytotoxicity in ALL cells. • The inhibition of ATR-CHK1 pathway induces aberrant chromosome segregation and mitotic spindle defects in doxorubicin-pretreated ALL cells.

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