DNA topoisomerase II, genotoxicity, and cancer

McClendon, A. Kathleen; Osheroff, Neil

doi:10.1016/j.mrfmmm.2007.06.009

Cited by 363 publications

(487 citation statements)

References 167 publications

(345 reference statements)

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“…As an abundant nuclear protein, topo II␣ is involved in several processes throughout the cell cycle, including transcription, DNA replication, chromatin recombination and organization, and regulation of the G2 decatenation checkpoint (Wang, 1996;Nitiss, 1998;Fortune and Osheroff, 2000;Champoux, 2001;Wang, 2002;McClendon and Osheroff, 2007). It is possible that the topo II␣ we consistently found associated with endogenous APC and with the M2-APC fragment ( Figures 1B and 6B) corresponds to a specific pool of topo II␣ involved in regulation of the G2/M transition.…”

Section: Discussionmentioning

confidence: 93%

“…Topo II␣ enzyme catalyzes DNA topology changes by introducing doublestrand DNA breaks that facilitate DNA strand passage and subsequent DNA religation (Wang, 1996;Champoux, 2001;Fortune and Osheroff, 2001;McClendon and Osheroff, 2007). Topo II␣ has been implicated in several cellular functions such as DNA replication and chromosome condensation (Wang, 1996;Nitiss, 1998;Fortune and Osheroff, 2000;Champoux, 2001;Wang, 2002;McClendon and Osheroff, 2007), and it seems to be essential in the control of the G2/M decatenation checkpoint during cell division (Downes et al, 1994). Topo II␣ was also found to be deregulated in colon cancers, with its expression limited to the proliferative zone in the normal colon, but up-regulated and widespread in colon cancer tissue (Murphy et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Interaction between Tumor Suppressor Adenomatous Polyposis Coli and Topoisomerase IIα: Implication for the G2/M Transition

Wang

Azuma

Moore

et al. 2008

MBoC

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The tumor suppressor adenomatous polyposis coli (APC) is implicated in regulating multiple stages of the cell cycle. APC participation in G1/S is attributed to its recognized role in Wnt signaling. APC function in the G2/M transition is less well established. To identify novel protein partners of APC that regulate the G2/M transition, APC was immunoprecipitated from colon cell lysates and associated proteins were analyzed by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF). Topoisomerase II␣ (topo II␣) was identified as a potential binding partner of APC. Topo II␣ is a critical regulator of G2/M transition. Evidence supporting an interaction between endogenous APC and topo II␣ was obtained by coimmunoprecipitation, colocalization, and Fö rster resonance energy transfer (FRET). The 15-amino acid repeat region of APC (M2-APC) interacted with topo II␣ when expressed as a green fluorescent protein (GFP)-fusion protein in vivo.Although lacking defined nuclear localization signals (NLS) M2-APC predominantly localized to the nucleus. Furthermore, cells expressing M2-APC displayed condensed or fragmented nuclei, and they were arrested in the G2 phase of the cell cycle. Although M2-APC contains a ␤-catenin binding domain, biochemical studies failed to implicate ␤-catenin in the observed phenotype. Finally, purified recombinant M2-APC enhanced topo II␣ activity in vitro. Together, these data support a novel role for APC in the G2/M transition, potentially through association with topo II␣. INTRODUCTIONThe tumor suppressor protein adenomatous polyposis coli (APC) is inactivated in Ͼ80% of all colorectal cancers (Kinzler and Vogelstein, 1996). The detection of mutant APC in the earliest stages of polyp development supports the idea that mutation of APC is an initiating event in colon carcinogenesis. The most common form of APC mutation results in elimination of the carboxy-terminal half of the APC protein.Because APC is a large, multidomain protein, APC truncation is predicted to impact several cellular mechanisms, the extent of which we are only beginning to understand.There is accumulating evidence supporting a role for APC in the regulation of cell cycle. Overexpression of APC in NIH3T3 fibroblasts and colon cancer cell lines leads to G1 cell cycle arrest (Ishidate et al., 2000;Heinen et al., 2002), presumably by repressing transcription of Wnt targets such as cyclin D1. APC may also participate directly in mitosis because it is transiently hyperphosphorylated in the M phase of the cell cycle (Bhattacharjee et al., 1996), accumulates at the microtubule-organizing center (Olmeda et al., 2003), and associates with the kinetochore in dividing cells (Fodde et al., 2001;Kaplan et al., 2001). A role for APC in mitosis might be critical for regulation of genomic stability and proper chromosome segregation. APC stabilized by zinc treatment induces G2/M cell cycle arrest in colon cancer cells (Jaiswal and Narayan, 2004). However, to date, little is known about the underlying mechanism by which APC participat...

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Interaction between Tumor Suppressor Adenomatous Polyposis Coli and Topoisomerase IIα: Implication for the G2/M Transition

Wang

Azuma

Moore

et al. 2008

MBoC

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“…29 Among these agents, the so called TOPOpoisons increase the levels of enzyme-DNA cleavable complexes by interacting with topoisomerase II at the protein-DNA interface in a non-covalent manner or covalently modifying the structure of the protein and/or the DNA. 30 In this context, the genotoxic activity of some human dietary components such as bioflavonoid has been attributed to their action as topoisomerase poisons. 5 In this study, we demonstrate through docking simulations that RSV polar groups allow this molecule to establish non-covalent cross-linking interactions with both TOPOII and DNA at the binding interface between these two macromolecules.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol acts as a topoisomerase II poison in human glioma cells

Leone

Basso

Polticelli

et al. 2012

Intl Journal of Cancer

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Recently, we demonstrated that Resveratrol (RSV), a well known natural stilbene, is able to induce a delay in S progression with a concomitant increase in cH2AX expression in U87 glioma cells. Furthermore, we showed that it inhibits the ability of recombinant human topoisomerase IIa to decatenate kDNA in vitro. Because proliferating tumor cells express topoisomerases at high levels and these enzymes are important targets of some of the most successful anticancer drugs, we tested whether RSV is able to poison topoisomerase IIa in glioma cells. Then, we monitored the increase of micronuclei in RSV treated U87 cells as a consequence of the conversion of TOPOII/DNA cleavable complexes to permanent DNA damage. Finally, we assayed the ability of RSV in modulating the expression of target proteins involved in DNA damage signalling, namely ATR, ATM, Chk1, Chk2 and cH2AX. Through a molecular modelling here we show that RSV binds at the TOPOII/DNA interface thus establishing several hydrogen bonds. Moreover, we show that RSV poisons TOPOIIa so inducing DNA damage; ATM, Chk2 and cH2AX are involved in the DNA damage signalling after RSV treatment.Resveratrol (3,4 0 ,5-trihydroxylstilbene), a polyphenol synthesized by a wide variety of plant species, is well known for its antitumor potential as demonstrated by many in vitro studies. 1 Nevertheless, the molecular targets of Resveratrol (RSV) activity seem not yet completely understood due to the multiplicity of RSV treatment effects in normal and transformed cultured cells. However, it is well known that RSV can disturb the normal progress of the cell cycle so decreasing the proliferation and can also induce apoptosis in cell type-and concentration-dependent mode. 2 On the other hand RSV, such as many other natural polyphenols, acts as antioxidant or prooxidant due to the intracellular presence of transition metal ions. The prooxidant activity could be an important action mechanism for its anticancer properties. 3 It has been suggested that some of the cellular effects of polyphenols, such as anti-proliferative and proapoptotic actions, could be correlated with their ability to act on topoisomerases. 4,5 These are ubiquitous nuclear enzymes that modulate the topological state of DNA by breaking and resealing one or both strands of a DNA duplex. In eukaryotic cells, type II topoisomerases, isoforms a and b, function during major cellular processes involving DNA (recombination, replication, proper chromosome structure and segregation) generating intermediate cleavable or covalent complexes with a short half-life. 6 Highly proliferating tumor cells express these enzymes, particularly Type IIa, at levels many times higher than quiescent cells 7,8 so that topoisomerases II are important targets for some of the anticancer drugs most successfully used in the treatment of human malignancies. TOPOII-targeted agents interfere with the binding between DNA and TOPOII or act by increasing the concentration of topoisomerase-DNA covalent complexes. These agents shifting the equilibrium of t...

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“…1.1 Introduction to the compound chemistry/clinical efficacy Type II topoisomerase enzymes have been described previously as 'the magicians of the DNA world' [25] and are essential for survival of eukaryotic cells [25][26][27][28]. These nuclear enzymes solve the topological problems that arise during cell replication, disentangling DNA that becomes under or over wound and are essential to maintain correct chromosome condensation, decongestion and segregation.…”

Section: Drug Evaluationmentioning

confidence: 99%