Topoisomerase IIIα is required for normal proliferation and telomere stability in alternative lengthening of telomeres

Temime-Smaali, Nassima; Guittat, Lionel; Wenner, Thomas; Bayart, Émilie; Douarre, Céline; Gómez, Dennis; Giraud-Panis, Marie-Josèphe; Londoño-Vallejo, Arturo; Gilson, Éric; Amor‐Guéret, Mounira; Riou, Jean‐François

doi:10.1038/emboj.2008.74

Cited by 43 publications

(73 citation statements)

References 56 publications

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“…Our and other studies (48) have also revealed that hTOP3a is essential in certain cell lines. Consistently, the sh-hTOP3a-mediated lethality in HEK293T cells was confirmed by increases in the sub-G 1 population of HEK293T sh-hTOP3a cells at 3 or 4 days after viral infection (data not shown).…”

Section: Discussionsupporting

confidence: 80%

DNA Topoisomerase III Alpha Regulates p53-Mediated Tumor Suppression

Hsieh

Fan

Chang

et al. 2014

Clinical Cancer Research

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Purpose: Human DNA topoisomerase III alpha (hTOP3a) is involved in DNA repair surveillance and cell-cycle checkpoints possibly through formatting complex with tumor suppressors. However, its role in cancer development remained unsolved.Experimental Design: Coimmunoprecipitation, sucrose gradient, chromatin immunoprecipitation (ChIP), real time PCR, and immunoblotting analyses were performed to determine interactions of hTOP3a with p53. Paired cell lines with different hTOP3a levels were generated via ectopic expression and short hairpin RNA (shRNA)-mediated knockdown approaches. Cellular tumorigenic properties were analyzed using cell counting, colony formation, senescence, soft agar assays, and mouse xenograft models.Results: The hTOP3a isozyme binds to p53 and cofractionizes with p53 in gradients differing from fractions containing hTOP3a and BLM. Knockdown of hTOP3a expression (sh-hTOP3a) caused a higher anchorage-independent growth of nontumorigenic RHEK-1 cells. Similarly, sh-hTOP3a and ectopic expression of hTOP3a in cancer cell lines caused increased and reduced tumorigenic abilities, respectively. Genetic and mutation experiments revealed that functional hTOP3a, p53, and p21 are required for this tumor-suppressive activity. Mechanism-wise, ChIP data revealed that hTOP3a binds to the p53 and p21 promoters and positively regulates their expression. Two proteins affect promoter recruitments of each other and collaborate in p21 expression. Moreover, sh-hTOP3a and sh-p53 in AGS cells caused a similar reduction in senescence and hTOP3a mRNA levels were lower in gastric and renal tumor samples.Conclusion: We concluded that hTOP3a interacts with p53, regulates p53 and p21 expression, and contributes to the p53-mediated tumor suppression.

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Section: Discussionsupporting

confidence: 80%

DNA Topoisomerase III Alpha Regulates p53-Mediated Tumor Suppression

Hsieh

Fan

Chang

et al. 2014

Clinical Cancer Research

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“…in the N-terminal region of BLM and is important for maintaining genomic stability in human cells (31). Another recent study has suggested a role for topoisomerase III␣ in ALT (32), as a direct interaction between TOPOIII␣ and BLM was demonstrated in cells using ALT as well as in in vitro experiments. The interaction of TOPOII␣ with BLM in cells using ALT supports the idea that topoisomerases are critically involved in pathways of telomere length maintenance in the absence of telomerase, most likely during the resolution of entangled telomere ends.…”

Section: Discussionmentioning

confidence: 97%

Telomerase-associated Protein 1, HSP90, and Topoisomerase IIα Associate Directly with the BLM Helicase in Immortalized Cells Using ALT and Modulate Its Helicase Activity Using Telomeric DNA Substrates

Bhattacharyya

Keirsey

Russell

et al. 2009

Journal of Biological Chemistry

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The BLM helicase associates with the telomere structural proteins TRF1 and TRF2 in immortalized cells using the alternative lengthening of telomere (ALT) pathways. This work focuses on identifying protein partners of BLM in cells using ALT. Mass spectrometry and immunoprecipitation techniques have identified three proteins that bind directly to BLM and TRF2 in ALT cells: telomerase-associated protein 1 (TEP1), heat shock protein 90 (HSP90), and topoisomerase II␣ (TOPOII␣). BLM predominantly co-localizes with these proteins in foci actively synthesizing DNA during late S and G 2 /M phases of the cell cycle when ALT is thought to occur. Immunoprecipitation studies also indicate that only HSP90 and TOPOII␣ are components of a specific complex containing BLM, TRF1, and TRF2 but that this complex does not include TEP1. TEP1, TOPOII␣, and HSP90 interact directly with BLM in vitro and modulate its helicase activity on telomere-like DNA substrates but not on nontelomeric substrates. Initial studies suggest that knockdown of BLM in ALT cells reduces average telomere length but does not do so in cells using telomerase. Bloom syndrome (BS)4 is a genetic disease caused by mutation of both copies of the human BLM gene. It is characterized by sun sensitivity, small stature, immunodeficiency, male infertility, and an increased susceptibility to cancer of all sites and types. The high incidence of spontaneous chromosome breakage and other unique chromosomal anomalies in cells from BS patients indicate an increase in homologous recombination in somatic cells (1). Another notable feature of non-immortalized and immortalized cells from BS individuals is the presence of telomeric associations (TAs) between homologous chromosomes (2). Work from our group and others have suggested a role for BLM in recombination-mediated mechanisms of telomere elongation or ALT (alternative lengthening of telomeres), processes that maintain/elongate telomeres in the absence of telomerase (3-5). However, the exact mechanism by which BLM contributes to telomere stability is unknown.Several proteins interact with and regulate BLM helicase activity, including two telomere-specific proteins, TRF1 and TRF2 (6, 7). Although TRF2 stimulates BLM unwinding of telomeric and non-telomeric 3Ј-overhang substrates, TRF1 inhibits BLM unwinding of telomeric substrates. TRF2-mediated stimulation of BLM helicase activity on a telomeric substrate is observed when TRF2 is present in excess or with equimolar amount of TRF1 but not when TRF1 is present in molar excess. Both proteins associate with BLM specifically in ALT cells in vivo, suggesting their involvement in the ALT pathways. In addition to TRF1 and TRF2, the telomere single-strand DNAbinding protein POT1 strongly stimulates BLM helicase activity on long telomeric forked duplexes and D-loop structures (8).Other proteins also play an important role in telomere maintenance in telomerase-negative cells, including RAD50, NBS1, and MRE11, which co-localize with TRF1 and TRF2 in specialized ALT-associated promyelocytic ...

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“…Inhibition of topoisomerase II, topoisomerase III or inhibition of DNA replication (preventing the normal resolution of single stranded parental DNA duplex intertwines) leads to a widespread increase in the number of anaphase bridges [11,12,30,83,[94][95][96]. So anaphase bridges can be instigated by an excess of any of the SCI discussed in this review.…”

Section: Visualisation Of Sci During Anaphasementioning

confidence: 98%

“Breaking Up Is Hard to Do”: The Formation and Resolution of Sister Chromatid Intertwines

Baxter

2015

Journal of Molecular Biology

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Topoisomerase IIIα is required for normal proliferation and telomere stability in alternative lengthening of telomeres

Cited by 43 publications

References 56 publications

DNA Topoisomerase III Alpha Regulates p53-Mediated Tumor Suppression

DNA Topoisomerase III Alpha Regulates p53-Mediated Tumor Suppression

Telomerase-associated Protein 1, HSP90, and Topoisomerase IIα Associate Directly with the BLM Helicase in Immortalized Cells Using ALT and Modulate Its Helicase Activity Using Telomeric DNA Substrates

“Breaking Up Is Hard to Do”: The Formation and Resolution of Sister Chromatid Intertwines

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