Regions within the N-terminal Domain of Human Topoisomerase I Exert Important Functions During Strand Rotation and DNA Binding

Frøhlich, Rikke; Andersen, Félicie F.; Westergaard, Ole; Andersen, Anders H.; Knudsen, Birgitta R.

doi:10.1016/j.jmb.2003.12.007

Cited by 30 publications

(44 citation statements)

References 37 publications

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“…The NH 2 -terminal region is unstructured and not required for catalytic activity but is required for nuclear localization and the physiologic response of Topo I to DNA damage (27). The region 191 to 206 regulates strand rotation and is critical for blunt-end ligation by Topo I (30). The linker region is not essential for enzymatic activity but forms a coiled coil motif that juts out from the active part of the enzyme and is believed to regulate the rate of DNA unwinding (31).…”

Section: Resultsmentioning

confidence: 99%

NKX3.1 Homeodomain Protein Binds to Topoisomerase I and Enhances Its Activity

Cai

Stuart

et al. 2007

Cancer Research

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Section: Resultsmentioning

confidence: 99%

NKX3.1 Homeodomain Protein Binds to Topoisomerase I and Enhances Its Activity

Cai

Stuart

et al. 2007

Cancer Research

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“…10,11 Top1 relaxes DNA supercoiling by producing transient Top1 cleavage complexes (Top1cc), which are Top1-linked DNA single-strand breaks. [10][11][12] Both positive and negative DNA supercoiling are produced ahead of and behind the elongating Pol II, respectively. 13 Top1 can remove both positive and negative supercoiling, 10,11 and therefore it can relax DNA on both sides of transcription complexes.…”

Section: Introductionmentioning

confidence: 99%

Hyperphosphorylation of RNA Polymerase II in Response to Topoisomerase I Cleavage Complexes and Its Association with Transcription- and BRCA1-dependent Degradation of Topoisomerase I

Sordet

Larochelle

Nicolas

et al. 2008

Journal of Molecular Biology

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SUMMARYThe progression of RNA polymerase II can be blocked by lesions on the DNA template. In this study, we focused in the modifications of the largest subunit of RNA polymerase II, Rpb1, in response to stabilized topoisomerase I (Top1)-DNA cleavage complexes. In addition to DNA modifications (base damages and strand breaks), Top1 cleavage complexes can be trapped by camptothecin and its derivatives used in cancer treatment. We find that, within a few minutes, camptothecin produces the complete hyperphosphorylation of Rpb1 in both primary and transformed cancer cells. Hyperphosphorylation is rapidly reversible following camptothecin removal. Hyperphosphorylation occurs selectively on the serine-5 residue of the conserved heptapeptide repeats in the Rpb1-carboxyterminal domain and is mediated principally by the TFIIH-associated kinase, Cdk7. Hyperphosphorylated Rpb1 is not primarily targeted for proteosomal degradation, but instead is subjected to cycles of phosphorylation and dephosphorylation as long as Top1 cleavage complexes are trapped by camptothecin. Finally, we show that transcription-induced degradation of Top1 is Brca1-dependent, suggesting a role for Brca1 in the repair or removal of transcription-blocking Top1-DNA cleavage complexes.

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“…The crystal structure of topoisomerase I was reported (6) but the NH 2 -terminal domain was not included and the function of this domain is unclear. The NH 2 -terminal domain is known to be dispensable for enzyme activity but plays an important role in the behavior of topoisomerase I including its sensitivity to camptothecin in vitro (7)(8)(9) It has four nuclear localization signals and binding sites for several proteins such as: nucleolin (10), SV40 large T antigen (11,12), TATA-binding protein (13), and RING/SR proteins (14). Therefore, the NH 2 -terminal domain seems to influence the localization of topoisomerase I inside the cell (15,16) and has regulatory functions through interaction with other proteins.…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase-1 Could Facilitate the Religation of Topoisomerase I-linked DNA Inhibited by Camptothecin

Park

Cheng

2005

Cancer Research

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Poly(ADP-ribose) polymerase-1 (PARP-1) is known to have an important role in camptothecin sensitivity and interacts with topoisomerase I. In the present study, the impact of PARP-1 on the topoisomerase I-DNA complex stabilized by camptothecin was assessed. It was shown that NH 2 terminustruncated topoisomerase I (amino acids 201-765) showed at least 4-fold less sensitivity to camptothecin than full-length topoisomerase I in the oligonucleotide religation assay. PARP-1 could prevent the action of camptothecin on the religation activity of full-length topoisomerase I, which is linked to DNA in a stoichiometrical manner. However, the religation activity of NH 2 terminus-truncated topoisomerase I, which is linked to DNA, could not be enhanced by PARP-1 in the presence of camptothecin. Both full-length and NH 2 terminus-truncated topoisomerase I interact with PARP-1. This data suggests that PARP-1 destabilizes the topoisomerase I-camptothecin-DNA complex with the participation of the NH 2 -terminal domain of topoisomerase I. Poly(ADP-ribosyl)ation of topoisomerase I by PARP-1 in the presence its substrate, NAD, could also promote the religation activity of full-length topoisomerase I as well as NH 2 terminus-truncated topoisomerase I. PARP-1 inhibitors (3-aminobenzamide, PJ34) could inhibit this process. Therefore, PARP-1 could facilitate the religation activity of topoisomerase I by itself through topoisomerase I-PARP-1 interaction (PARP-1 action) or by the formation of poly(ADP-ribosyl)ation of topoisomerase I (PARP-1/NAD action). This study also implies that PARP-1 and PARP-1/ NAD actions need to be highly regulated by cellular factors for camptothecin to exert its cytotoxicity inside the cells. We propose ATP to be one of the important regulatory factors. (Cancer Res 2005; 65(9): 3894-902)

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Regions within the N-terminal Domain of Human Topoisomerase I Exert Important Functions During Strand Rotation and DNA Binding

Cited by 30 publications

References 37 publications

NKX3.1 Homeodomain Protein Binds to Topoisomerase I and Enhances Its Activity

NKX3.1 Homeodomain Protein Binds to Topoisomerase I and Enhances Its Activity

Hyperphosphorylation of RNA Polymerase II in Response to Topoisomerase I Cleavage Complexes and Its Association with Transcription- and BRCA1-dependent Degradation of Topoisomerase I

Poly(ADP-Ribose) Polymerase-1 Could Facilitate the Religation of Topoisomerase I-linked DNA Inhibited by Camptothecin

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