Transcription-Dependent Degradation of Topoisomerase I-DNA Covalent Complexes

Desai, Shyamal D.; Zhang, Hui; Rodriguez-Bauman, Alexandra; Yang, Jin Ming; Wu, Xiaohua; Gounder, Murugesan; Rubin, Eric H.; Liu, Leroy F.

doi:10.1128/mcb.23.7.2341-2350.2003

Cited by 138 publications

(168 citation statements)

References 28 publications

(45 reference statements)

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“…The antitumor activity of CPT mainly results from its specific interference with the breakage-reunion reaction of Top1, which causes the reversible formation of covalently cleavable complexes consisting of Top1, CPT and DNA (Desai et al, 2001). Most of the downstream effects caused by cleavable complex are viewed as DNA damage responses, including p53 stabilization, G 2 -phase arrest, nuclear factor-kB activation and replication protein A phosphorylation (Shao et al, 1999;Huang et al, 2000;Desai et al, 2001;Li and Liu, 2001). CPT has been previously reported to induce p53 phosphorylation at Ser15 through the ATM/Chk2 activation (Zhao et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…CPT-induced degradation of MLL5 independent of ATM and requires active DNA replication CPT-induced degradation of proteins, such as Top1, exhibited a high degree of heterogeneity among different cell types (Desai et al, 2001). Therefore, we tested if downregulation of MLL5 by CPT was cell type-dependent.…”

Section: Camptothecin Promotes Degradation Of Mll5mentioning

confidence: 99%

“…CPT induces downregulation of Cdc25A, which potentiates the S and G 2 /M cell cycle checkpoints and prevents propagation of damaged DNA (Xiao et al, 2003). Top1 is also found effectively degraded by CPT in non-transformed, but not in transformed cells (Desai et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

et al. 2011

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Mixed lineage leukemia 5 (MLL5) has been implicated in multiple aspects of cell physiology, such as hematopoiesis, cell cycle control and chromatin regulatory network. In this study, we present evidence that MLL5 is involved in the camptothecin (CPT)-induced p53 activation. CPT promoted the degradation of MLL5 protein in a time-and dose-dependent manner in actively replicating cells. The downregulation of MLL5 led to phosphorylation of p53 at Ser392, which was abrogated by exogenous overexpression of MLL5. In MLL5-knockdown cells, p53 protein was stabilized and bound to DNA with higher affinity, leading to activation of downstream genes. Co-immunoprecipitation showed that MLL5 preferentially interacted with the tetramerized form of p53, and knockdown of MLL5 promoted chromatin accumulation of p53 tetramers, suggesting that the association of MLL5 with p53 may prevent the p53 tetramers from binding to the chromatin target sites. The role of MLL5 in CPT-induced p53 activation was conserved in developing zebrafish, where CPT downregulated zebrafish Mll5 protein, and the microinjection of zebrafish mll5 mRNA substantially blocked the CPT-induced apoptosis. In summary, our study proposed MLL5 as a novel component in the regulation of p53 homeostasis and a new cellular determinant of CPT.

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Section: Discussionmentioning

confidence: 99%

Section: Camptothecin Promotes Degradation Of Mll5mentioning

confidence: 99%

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Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

et al. 2011

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“…47 In contrast, most tumour cells are defective in topoisomerase I degradation and unable to recover from transcriptional arrest. L. donovani is a unicellular protozoan parasite and it undergoes apoptosis-like death during treatment with CPT.…”

Section: Discussionmentioning

confidence: 99%

Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani

et al. 2004

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The parasites of the order kinetoplastidae including Leishmania spp. emerge from most ancient phylogenic branches of unicellular eukaryotic lineages. In their life cycle, topoisomerase I plays a significant role in carrying out vital cellular processes. Camptothecin (CPT), an inhibitor of DNA topoisomerase I, induces programmed cell death (PCD) both in the amastigotes and promastigotes form of L. donovani parasites. CPT-induced cellular dysfunction in L. donovani promastigotes is characterized by several cytoplasmic and nuclear features of apoptosis. CPT inhibits cellular respiration that results in mitochondrial hyperpolarization taking place by oligomycin-sensitive F0-F1 ATPase-like protein in leishmanial cells. During the early phase of activation, there is an increase in reactive oxygen species (ROS) inside cells, which causes subsequent elevation in the level of lipid peroxidation and decrease in reducing equivalents like GSH. Endogenous ROS formation and lipid peroxidation cause eventual loss of mitochondrial membrane potential. Furthermore, cytochrome c is released into the cytosol in a manner independent of involvement of CED3/CPP32 group of proteases and unlike mammalian cells it is insensitive to cyclosporin A. These events are followed by activation of both CED3/CPP32 and ICE group of proteases in PCD of Leishmania. Taken together, our study indicates that different biochemical events leading to apoptosis in leishmanial cells provide information that could be exploited to develop newer potential therapeutic targets.

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“…Xu et al 28 then showed that BTBD1 and BTBD2 were able to bind. Further studies on BTBD1 and BTBD2 are thus required to fill in the gaps concerning molecular events that regulate Topo1 activity, its involvement in vital biological functions such as mitosis and transcription, 3,[36][37][38] and in severe pathologies such as cancer and leukaemia. [15][16][17][18][19][20] Here we attempted to elucidate BTBD1 function in skeletal muscle, where this protein is mostly expressed.…”

Section: Discussionmentioning

confidence: 99%

The topoisomerase 1-interacting protein BTBD1 is essential for muscle cell differentiation

et al. 2004

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DNA topoisomerase I (Topo1) contributes to vital biological functions, but its regulation is not clearly understood. The BTBD1 protein was recently cloned on the basis of its interaction with the core domain of Topo1 and is expressed particularly in skeletal muscle. To determine BTBD1 functions in this tissue, the in vitro model used was the C2C12 mouse muscle cell line, which expresses BTBD1 mainly after myotube differentiation. We studied the effects of a stably overexpressed BTBD1 protein truncated of the 108 N-terminal amino-acid residues and harbouring a C-terminal FLAG tag (D-BTBD1). The proliferation speed of D-BTBD1 C2C12 cells was significantly decreased and no myogenic differentiation was observed, although these cells maintained their capacity to enter adipocyte differentiation. These alterations could be related to Topo1 deregulation. This hypothesis is further supported by the decrease in nuclear Topo1 content in D-BTBTD1 proliferative C2C12 cells and the switch from the main peripheral nuclear localization of Topo1 to a mainly nuclear diffuse localization in D-BTBTD1 C2C12 cells. Finally, this study demonstrated that BTBD1 is essential for myogenic differentiation.

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Transcription-Dependent Degradation of Topoisomerase I-DNA Covalent Complexes

Cited by 138 publications

References 28 publications

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani

The topoisomerase 1-interacting protein BTBD1 is essential for muscle cell differentiation

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