Since the report of \"DNA untwisting\" activity in 1972, ∼50 years of research has revealed seven topoisomerases in humans (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α, TOP3β and Spo11). These conserved regulators of DNA topology catalyze controlled breakage to the DNA backbone to relieve the torsional stress that accumulates during essential DNA transactions including DNA replication, transcription, and DNA repair. Each topoisomerase-catalyzed reaction involves the formation of a topoisomerase cleavage complex (TOPcc), a covalent protein-DNA reaction intermediate formed between the DNA phosphodiester backbone and a topoisomerase catalytic tyrosine residue. A variety of perturbations to topoisomerase reaction cycles can trigger failure of the enzyme to re-ligate the broken DNA strand(s), thereby generating topoisomerase DNA-protein crosslinks (TOP-DPC). TOP-DPCs pose unique threats to genomic integrity. These complex lesions are comprised of structurally diverse protein components covalently linked to genomic DNA, which are bulky DNA adducts that can directly impact progression of the transcription and DNA replication apparatus. A variety of genome maintenance pathways have evolved to recognize and resolve TOP-DPCs. Eukaryotic cells harbor tyrosyl DNA phosphodiesterases (TDPs) that directly reverse 3\'-phosphotyrosyl (TDP1) and 5\'-phoshotyrosyl (TDP2) protein-DNA linkages. The broad specificity Mre11-Rad50-Nbs1 and APE2 nucleases are also critical for mitigating topoisomerase-generated DNA damage. These DNA-protein crosslink metabolizing enzymes are further enabled by proteolytic degradation, with the proteasome, Spartan, GCNA, Ddi2, and FAM111A proteases implicated thus far. Strategies to target, unfold, and degrade the protein component of TOP-DPCs have evolved as well. Here we survey mechanisms for addressing Topoisomerase 1 (TOP1) and Topoisomerase 2 (TOP2) DPCs, highlighting systems for which molecular structure information has illuminated function of these critical DNA damage response pathways.

The long noncoding RNAs (lncRNAs) have been shown to actively participate in various biological processes including cancer progression. However, most lncRNAs still have undefined functions. In current work, we identified a novel lncRNA named LALTOP which displayed an oncogenic function in non-small cell lung cancer (NSCLC). LALTOP expression is increased in NSCLC tissues and cell lines. Moreover, LALTOP strongly promoted proliferation and migration of A549 and H1793 cells. RNA-RNA interaction assay showed that LALTOP bound and stabilized topoisomerase II alpha (Top2α) mRNA. Positive correlation can be found between LALTOP and Top2α mRNA expressions in clinical specimens. ASOs targeting LALTOP could markedly inhibit malignant phenotypes of NSCLC. Collectively, LALTOP may serve as an oncogenic lncRNA and enhances NSCLC progression. Targeting LALTOP has therapeutic potential for eradicating lung cancer cells.

UNASSIGNED: Studies have confirmed that parts of the non-coding genes in the human genome play an important role in the pathogenesis and metastasis of prostate cancer. Among them, long non-coding RNAs (lncRNAs) are vitally involved in the biological regulation of prostate cancer. In addition, lncRNAs are closely associated with the recurrence, metastasis and prognosis of prostate cancer. However, the molecular pathogenesis of lncRNAs in regulating cell growth and metastasis of prostate cancer remains unclear. Therefore, this study was designed to explore the function and mechanism of lncRNA RAMS11 in cell growth and metastasis of prostate cancer.
UNASSIGNED: Prostate cancer and para-carcinoma tissue samples were obtained from 42 patients who were diagnosed from March 2013 to September 2014 at Quanzhou First Hospital Affiliated to Fujian Medical University. Microarray experiments and real-time polymerase chain reaction (PCR) measured the expression of lncRNA. RWPE-2, LNCap, PC3 and DU145 cells were used for an in vitro model.
UNASSIGNED: The expression of lncRNA RAMS11 was up-regulated in prostate cancer tissue samples. LncRNA RAMS11 promoted cell growth and metastasis of prostate cancer cells. Down-regulation of lncRNA RAMS11 attenuated cell growth and metastasis of prostate cancer cells. We also demonstrated that lncRNA RAMS11 bound to CBX4 to activate expression of Top2α. LncRNA RAMS11 promoted tumor growth of prostate cancer in the mouse model. The inhibition of CBX4 attenuated the pro-cancer effects of lncRNA AMS11 in prostate cancer cells, while the activation of Top2α attenuated the anti-cancer effects of si-lncRNA RAMS11 in prostate cancer cells.
UNASSIGNED: Our results indicated that lncRNA RAMS11 promoted cell growth and metastasis of prostate cancer by CBX4 complex via binding to Top2α, and might be developed for the treatment of prostate cancer.

FAM122A is a housekeeping gene and highly conserved in mammals. More recently, we have demonstrated that FAM122A is essential for maintaining the growth of hepatocellular carcinoma cells, in which we unexpectedly found that FAM122A deletion increases γH2AX protein level, suggesting that FAM122A may participate in the regulation of DNA homeostasis or stability. In this study, we continued to investigate the potential role of FAM122A in DNA damage and/or repair. We found that CRISPR/Cas9-mediated FAM122A deletion enhances endogenous DNA damages in cancer cells but not in normal cells, demonstrating a significant increase in γH2AX protein and foci formation of γH2AX and 53BP1, as well as DNA breaks by comet assay. Further, we found that FAM122A deletion greatly increases TOP2α protein level, and significantly and specifically enhances TOP2 poisons (etoposide and doxorubicin)-induced DNA damage effects in cancer cells. Moreover, FAM122A is found to be interacted with TOP2α, instead of TOP2β. However, FAM122A knockout doesn\'t affect the intracellular ROS levels and the process of DNA repair after removal of etoposide with short-term stimulation, suggesting that FAM122A deletion-enhanced DNA damage does not result from endogenous overproduction of ROS and/or impairment of DNA repair ability. Collectively, our study provides the first demonstration that FAM122A is critical for maintaining DNA stability probably by modulating TOP2α protein, and FAM122A deletion combined with TOP2-targeted drugs may represent a potential novel chemotherapeutic strategy for cancer patients.

In humans, the ERBB2 gene amplification and overexpression are biomarkers for invasive breast cancer and a therapeutic target. Also, TOP2α gene aberrations predict the response to anthracycline-based adjuvant chemotherapy. Although feline mammary tumors (FMTs) are good models in comparative oncology, scarce data is available regarding the ERBB2 and TOP2α status. In this study, and for the first time, the ERBB2 DNA status and RNA levels of intracellular (ICD) and extracellular (ECD) coding regions were compared with TOP2α gene status and expression profile, in samples of FMTs and disease-free tissues from the same animal. Results showed that ERBB2 and TOP2α gene status are highly correlated (r=0.87, p<0.0001, n=25), with few tumor samples presenting amplification. Also, the majority of the FMTs showed ERBB2 overexpression coupled with TOP2α overexpression (r=0.87, p<0.0001, n=27), being the ERBB2-ICD and ECD transcripts highly correlated (r=0.97, p<0.0001, n=27). Significant associations were found between TOP2α gene status or ERBB2 and TOP2α RNA levels with several clinicopathological parameters. This work highlights the need of experimental designs for a precise evaluation of ERBB2 and TOP2α gene status and its expression in FMTs, to improve their clinical management and to further validate them as a suitable model for comparative oncology studies.

The Eighth International Biennial Conference on RNA polymerases I and III (the \'Odd Pols\') was held June 7-11, 2012 at The Airlie Center in Warrenton Virginia, USA. It was sponsored by the Universite Laval and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, and organized by Rich Maraia and Tom Moss. The meeting honored the memory of Pierre Thuriaux (Jan 1, 1950-March 18, 2012) and David Schneider reminisced on the important accomplishments his mentor Masayasu Nomura (1927-2011). The goal of the conference was to bring together the world\'s experts on RNA polymerase I and RNA polymerase III to highlight and share their latest results and varied experimental approaches. The meeting drew attendees from twelve countries and most contributed through oral and poster presentations. The talks were organized into several sessions subdivided into 10 distinct topics. The keynote speaker, Ian Willis, opened the meeting with his presentation entitled \"New Regulators of Signaling to Odd Pols\" and the closing presentation was given by Patrick Cramer with his presentation \"Conservation of the RNA polymerase I, II and III transcription initiation machineries\". Here we present some of the highlights from the meeting using summaries provided by the participants.