The G2 DNA Damage Checkpoint Delays Expression of Genes Encoding Mitotic Regulators

Crawford, David F.; Piwnica‐Worms, Helen

doi:10.1074/jbc.m103414200

Cited by 71 publications

(74 citation statements)

References 60 publications

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“…Cell cycle phase-specific expression of UBE2Q2 The EST (AA476260) representing UBE2Q2 in our microarray study (Crawford and Piwnica-Worms, 2001) is now referred to as UBE2Q2 or LOC92912 in GenBank and recent publications (Melner et al, 2006;Seghatoleslam et al, 2006). UBE2Q2 is very similar to another human protein known as UBE2Q1 (or NICE-5) and a C. elegans protein known as UBC-25 (Schulze et al, 2003).…”

Section: Resultsmentioning

confidence: 93%

“…One G2/M-specific gene identified in our microarray screen (Crawford and Piwnica-Worms, 2001) was a previously uncharacterized ubiquitin conjugating enzyme now referred to as UBE2Q2 (also LOC92912 and UBCi) (Melner et al, 2004;Seghatoleslam et al, 2006). In these studies, we have demonstrated that this protein likely functions as an E2 and that it plays an important role in the cellular response to microtubule inhibiting agents by regulating an early mitotic checkpoint.…”

Section: Introductionmentioning

confidence: 78%

“…Transfections, cell synchronization and drug treatments were performed according to established protocols, as detailed in the Supplementary information (Chen and Okayama, 1987;Crawford and Piwnica-Worms, 2001). …”

Section: Methodsmentioning

confidence: 99%

“…A microarray study identified several components of the ubiquitin-proteasome system as mitotic regulatory proteins (Crawford and Piwnica-Worms, 2001). Ubiquitinmediated protein degradation is known to play a pivotal role in regulation of diverse cellular processes including both normal cell cycle regulation (reviewed in Pray et al, 2002;Vodermaier, 2004) and cell cycle checkpoint function (Scolnick and Halazonetis, 2000;Lew and Burke, 2003;Matsusaka and Pines, 2004;Zhang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Inactivation of the ubiquitin conjugating enzyme UBE2Q2 causes a prophase arrest and enhanced apoptosis in response to microtubule inhibiting agents

2007

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A putative ubiquitin conjugating enzyme known as UBE2Q2 was previously identified in a microarray screen for mitotic regulatory proteins. UBE2Q2 is very similar to another human protein, UBE2Q1 and orthologs from other higher eukaryotic species. In these studies, we demonstrate that UBE2Q2 can covalently bind ubiquitin on the active site cysteine in vitro and show that inhibition of this protein in vivo causes an early mitotic arrest and increased cytotoxicity when cells are treated with microtubule inhibiting agents (MIAs). Changes in cell cycle progression and viability are not observed in the absence of MIA treatment, indicating that UBE2Q2 is involved in the response to MIAs rather than performing a more general function in mitosis. Inhibition of the UBE2Q2 protein causes cells to undergo a prolonged prophase arrest suggesting that UBE2Q2 normally functions to antagonize an early mitotic checkpoint. Furthermore, UBE2Q2 inhibition sensitizes cells to the cytotoxic effects of MIAs through caspase-mediated apoptosis that is correlated with PARP-1 cleavage. These data provide insights into the cellular response to MIAs and demonstrate that inhibition of UBE2Q2 protein function may be useful in the treatment of malignancies.

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Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inactivation of the ubiquitin conjugating enzyme UBE2Q2 causes a prophase arrest and enhanced apoptosis in response to microtubule inhibiting agents

2007

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“…It has been proven that when DNA damage occurs in G2 phase and cell cycle is arrested, several genes normally required for G2 and M phase become downregulated (Crawford and Piwnica-Worms, 2001;Chang et al, 2002;Ren et al, 2002). Interestingly, Jackson et al (2005) have demonstrated that especially pRb2/ p130 and p107 are critical regulators in the expression of G2/M required genes (e.g.…”

Section: Cell Cycle Checkpointsmentioning

confidence: 99%

Cell cycle control and beyond: emerging roles for the retinoblastoma gene family

et al. 2006

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Rb family proteins (pRb/p105, Rb2/p130 and p107) play a key role in cell cycle control and are worthily involved in transcription repression and tumor suppression. The mechanisms of transcriptional activation and repression by the Rb gene family has been extensively investigated: pRb, pRb2/p130 and p107 interact with different E2F family factors and can inhibit E2F responsive promoters, interfering with progression of cell cycle, gene transcription, initiation of apoptotic process and cell differentiation. Recent studies have indicated that Rb and Rb2/p130 may be involved in cellular response to DNA damage events, by influencing the transcription of factors involved in DNA repair pathways. In particular, evidences suggest that Rb loss and target gene deregulation impacts on the repair of UV-induced pyrimidine pyrimidone photoproducts (6-4 PP) by regulating the expression of several DNA damage factors involved in UV DNA damage repair processes, including proliferating cell nuclear antigen. Ongoing studies are focused on the mechanisms by which Rb family genes drive cell cycle exit following DNA damage induction, and how Rb gene family's interaction with chromatin remodeling factors can influence DNA repair dynamics.

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Regulation of the Cell Cycle, Cell Cycle Checkpoints, and Cancer

Delia

Buscemi

2007

The Cancer Handbook

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DNA damage response (DDR) pathways are triggered to ensure proper repair of DNA lesions and preserve genome integrity. Key intracellular transducers of the DNA damage are ataxia‐telangiectasia mutated kinase (ATM) and ataxia‐telangiectasia and Rad3‐related kinase (ATR). These nuclear proteins, through dynamic interaction with chromatin‐bound sensory components and phosphorylation at T/SQ residues of a multitude of substrates, including the checkpoint kinases Chk1 and Chk2, activate a network of pathways important for DNA repair, multiple cell cycle–phase arrest, transcription, and apoptosis. Interestingly, the DDR machinery is a key mediator of telomere‐dependent and telomere‐independent forms of cellular senescence, and provides a barrier to aberrant DNA replication induced by oncogenic stimuli. These findings and the constitutive activation of the DDR in human precancerous lesions, underscore the role of the DDR as a tumour suppressor constraining transformation by driving incipient tumour cells into apoptosis or senescence. Since genetic abnormalities of the DDR hypersensitize to genotoxic anticancer agents, this pathway represents a relevant target to increase tumour cell kill and possibly overcome drug resistance. The promising results with a number of chemical inhibitors of ATM, Chk1 and Chk2 are paving the way for new chemoradiation strategies that exploit the DDR machinery.

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The G2 DNA Damage Checkpoint Delays Expression of Genes Encoding Mitotic Regulators

Cited by 71 publications

References 60 publications

Inactivation of the ubiquitin conjugating enzyme UBE2Q2 causes a prophase arrest and enhanced apoptosis in response to microtubule inhibiting agents

Inactivation of the ubiquitin conjugating enzyme UBE2Q2 causes a prophase arrest and enhanced apoptosis in response to microtubule inhibiting agents

Cell cycle control and beyond: emerging roles for the retinoblastoma gene family

Regulation of the Cell Cycle, Cell Cycle Checkpoints, and Cancer

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