The Transcriptional Elongation Inhibitor 5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole Inhibits Transcription Factor IIH-associated Protein Kinase

Yankulov, Krassimir; Yamashita, Katsumi; Roy, Richard; Egly, Jean‐Marc; Bentley, David L.

doi:10.1074/jbc.270.41.23922

Cited by 168 publications

(167 citation statements)

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“…Furthermore, it has been suggested previously that blockage of RNA polymerase may trigger UV-induced apoptosis (Ljungman and Zhang, 1996). To investigate the possibility that stalled RNA pol II complexes may initiate this apoptotic process observed in A431 and MCF-7 cells, we used an RNA pol II inhibitor, 5,6-dichloro-1-b-D-ribofuranosylbenzimidazole (DRB), to completely block transcriptional activity (Yankulov et al, 1995). As with UVB-irradiation (Figure 1), DRB induced apoptosis as seen by the nucleosomal DNA ladder (Figure 10a) but also by the cleavage of poly(ADPribose) polymerase (PARP) to its 85 kDa fragment ( Figure 3B), the proteolytic hallmark of the apoptotic cell death process (Lazebnik et al, 1994).…”

Section: Resultsmentioning

confidence: 99%

“…Cells were irradiated without pretreatment (a) or preincubated 24 h with 500 mM mimosine (b) and harvested following incubation for the period indicated, as described in Materials and methods p21-induced G 1 arrest protects cells from apoptosis N Bissonnette and DJ Hunting event, and can be observed 2 h after irradiation of A431 cells (Figure 3a). Interestingly, PARP cleavage was also seen following treatment with an inhibitor of RNA pol II, DRB, a competitive inhibitor for both ATP and GTP (Zandomeni, 1989) and an e cient inhibitor of CAK, which can associate with the transcription factor IIH (Yankulov et al, 1995), in the absence of any obvious DNA damage (Figure 3b). However, the p21 Waf1/Cip1 dependent cell cycle arrest blocked PARP cleavage and protected cells from apoptosis.…”

Section: P21-dependent Cell Cycle Arrest In Late G 1 Protects A431 Cementioning

confidence: 99%

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p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage

1998

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Cells expressing the R273H mutant of p53, which lacks sequence speci®c DNA binding capacity, do not undergo cell cycle arrest in G 1 following exposure to ionizing or UV radiation because of their inability to induce p21 Waf1/Cip1 , a cyclin-dependent kinase inhibitor and downstream mediator of p53-dependent DNA damageinduced growth arrest. Following UV-irradiation or treatment with an inhibitor of RNA pol II, we observed a rapid induction of the apoptotic process, as evidenced by DNA fragmentation and the proteolytic cleavage of poly(ADP-ribose) polymerase. Using mimosine, a p21 Waf1/Cip1 inducer that bypasses the requirement for transcriptional transactivation by p53, we demonstrated that a G 1 cell cycle arrest can prevent apoptosis following UV-irradiation or treatment with an RNA polymerase II inhibitor. Serum starvation, which also synchronized cells in G 1 but did not induce p21 Waf1/Cip1 , did not protect cells from apoptosis. These results demonstrate that restoring a late G 1 checkpoint by inducing p21 Waf1/Cip1 expression can protect cells from DNA damage induced apoptosis. Our results suggest that p21 Waf1/Cip1 can interrupt the apoptotic process at a point downstream from p53 accumulation but upstream from caspase-3 activation.

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Section: Resultsmentioning

confidence: 99%

Section: P21-dependent Cell Cycle Arrest In Late G 1 Protects A431 Cementioning

confidence: 99%

p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage

1998

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“…Serum-dependent CTD phosphorylation correlates well with the activation of MAPKs, and depletion of ERK-1/2 from cell extracts results in a loss of serum-stimulated CTD kinase activity (Dubois et al, 1994). In addition, serum-stimulated CTD kinase activity is resistant to inhibiton by the drug 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) (Dubois et al, 1994;Bonnet et al, 1999), which inhibits CDK7, CDK8, and CDK9 but not ERK-1/2 CTD kinase (Marshall and Price, 1995;Yankulov et al, 1995;Rickert et al, 1999). Finally, recombinant ERK-1/2 has been shown to ef®ciently phosphorylate the RNAP II CTD in vitro (Trigon et al, 1998;Bonnet et al, 1999).…”

Section: Cdks Associated With the Rnap II Transcription Machinerymentioning

confidence: 99%

Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

Oelgeschläger

2002

Journal Cellular Physiology

127

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The carboxyl-terminal domain (CTD) of the largest subunit of mammalian RNA polymerase II (RNAP II) consists of 52 repeats of a consensus heptapeptide and is subject to phosphorylation and dephosphorylation events during each round of transcription. RNAP II activity is regulated during the cell cycle and cell cycledependend changes in RNAP II activity correlate well with CTD phosphorylation. In addition, global changes in the CTD phosphorylation status are observed in response to mitogenic or cytostatic signals such as growth factors, mitogens and DNA-damaging agents. Several CTD kinases are members of the cyclindependent kinase (CDK) superfamily and associate with transcription initiation complexes. Other CTD kinases implicated in cell cycle regulation include the mitogen-activated protein kinases ERK-1/2 and the c-Abl tyrosine kinase. These observations suggest that reversible RNAP II CTD phosphorylation may play a key role in linking cell cycle regulatory events to coordinated changes in transcription.

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“…The highly selective cdk inhibitor, Roscovitine, has recently been shown to inhibit RNA polymerase II-dependent transcription at a similar concentration to DRB (Sankrithi and Eskin, 1999) and share in common the ability to inhibit cyclin Hcdk7 activity (Yankulov et al, 1995;Hajduch et al, 1999). However, Roscovitine does not inhibit the DRB-sensitive enzymes CK2 or CK1.…”

Section: Inhibition Of Cyclin-dependent Kinases Is Sufficient To Sensmentioning

confidence: 99%

Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways

et al. 2000

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High level activation of p53-dependent transcription occurs following cellular exposure to genotoxic damaging agents such as UV-C, while ionizing radiation damage does not induce a similarly potent induction of p53-dependent gene expression. Reasoning that one of the major di erences between UV-C and ionizing radiation damage is that the latter does not inhibit general transcription, we attempted to reconstitute p53-dependent gene expression in ionizing irradiated cells by co-treatment with selected transcription inhibitors that alone do not activate p53. p53-dependent transcription can be dramatically enhanced by the treatment of ionizing irradiated cells with low doses of DRB, which on its own does not induce p53 activity. The mechanism of ionizing radiationdependent activation of p53-dependent transcription using DRB is more likely due to inhibition of gene transcription rather than prolonged DNA damage, as the non-genotoxic and general transcription inhibitor Roscovitine also synergistically activates p53 function in ionizing irradiated cells. These results identify two distinct signal transduction pathways that cooperate to fully activate p53-dependent gene expression: one responding to lesions induced by ionizing radiation and the second being a kinase pathway that regulates general RNA Polymerase II activity.

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The Transcriptional Elongation Inhibitor 5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole Inhibits Transcription Factor IIH-associated Protein Kinase

Cited by 168 publications

References 42 publications

p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage

p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage

Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways

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