Article
Oncology
Soo Fern L. Lee, Jayshree L. Hirpara, Jianhua Qu, Sanjiv K. Yadav, Karishma Sachaphibulkij, Shazib Pervaiz
Summary: A novel topoisomerase II alpha inhibitor, mercaptopyridine oxide (MPO), is reported to induce cell cycle arrest and senescence through different cell cycle regulators in different cell lines. The inhibition of topoisomerase II alpha is associated with ROS-mediated activation of ATM-Chk2 kinase axis, independent of p53 function. Additionally, the interaction between topoisomerase II alpha and Chk1 is important for decatenation checkpoint activation.
Article
Biochemistry & Molecular Biology
Afif F. Bandak, Tim R. Blower, Karin C. Nitiss, Viraj Shah, John L. Nitiss, James M. Berger
Summary: The ATPase domains of the enzyme are not required for DNA strand passage, but their loss elevates the enzyme's propensity for DNA damage. The unstructured C-terminal domains and cleavage-prone mutations enhance strand passage activity and sensitivity to the chemotherapeutic agent etoposide. In ATPase-less enzymes, the presence of CTD or mutations promote even greater levels of DNA cleavage.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Julia A. M. Bakx, Andreas S. Biebricher, Graeme A. King, Panagiotis Christodoulis, Kata Sarlos, Anna H. Bizard, Ian D. Hickson, Gijs J. L. Wuite, Erwin J. G. Peterman
Summary: Topoisomerase IIIa is a type 1A topoisomerase that forms a complex with RMI1 and RMI2 called TRR in human cells. In this study, the authors used optical tweezers and fluorescence microscopy to investigate the catalytic steps of TRR. They found that TRR forms an open gate in single-stranded DNA and can bind a second single-stranded or double-stranded DNA molecule, leading to catenation. Interestingly, double-stranded DNA binding increases the gate size and the helicase BLM affects the flexibility of the gate. These findings suggest that TRR-mediated transfer of double-stranded DNA may be more important than previously believed.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
M. Johansson, Y. Azuma, D. J. Clarke
Summary: DNA topoisomerase II (TopoII) plays a crucial role in mitosis by decatenating chromosomes. When the TopoII enzyme cycle stalls due to failed ATP hydrolysis, the onset of anaphase is delayed to ensure accurate chromosome segregation. Recent evidence shows that the TopoII checkpoint response requires Aurora B and Haspin kinases, and is triggered by SUMOylation of the C-terminal domain of TopoII.
Article
Oncology
Dilara Koyuncu, Utsav Sharma, Erik T. Goka, Marc E. Lippman
Summary: The study revealed that SAC genes were elevated in breast cancer, with BUB1B showing the most significant change. Overexpression of BUB1B was associated with decreased overall survival. Reduction of BUB1B expression led to decreased viability and clonogenicity in BrCa cell lines, increased apoptosis and cell death, as well as chromosomal abnormalities.
BREAST CANCER RESEARCH AND TREATMENT
(2021)
Article
Biochemistry & Molecular Biology
Mai A. E. Mourad, Ayman Abo Elmaaty, Islam Zaki, Ahmed A. E. Mourad, Amal Hofni, Ahmed E. Khodir, Esam M. Aboubakr, Ahmed Elkamhawy, Eun Joo Roh, Ahmed A. Al-Karmalawy
Summary: A novel series of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids were synthesized and evaluated for their inhibitory effects on topo IIa and EGFR as well as their ability to induce apoptosis. The compounds 6i, 6a, and 6c exhibited superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. Molecular analysis suggested that these hybrids could inhibit topo IIa and EGFR activities and cause cell cycle arrest and increased levels of p53, caspase-7, caspase-9, and Bax/Bcl-2 ratio.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Oncology
Xiao Lei, Kun Cao, Yuanyuan Chen, Hui Shen, Zhe Liu, Hongran Qin, Jianming Cai, Fu Gao, Yanyong Yang
Summary: The study identified TG2 as a new component of the DSB repair complex, which interacts directly with TOPOII alpha to promote repair. TG2 deficient cells lose the capacity for repair and become sensitive to ionizing radiation. Specific inhibition of the TG2-TOPOII alpha interaction can significantly inhibit repair and increase sensitivity in lung cancer cells.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2021)
Article
Multidisciplinary Sciences
Seyoun Byun, Kajsa E. Affolter, Angela K. Snow, Karen Curtin, Austin R. Cannon, Lisa A. Cannon-Albright, Ramya Thota, Deborah W. Neklason
Summary: This study identified significant methylation differences in NETs of the small intestine, with genes from the GPCR pathways being overrepresented in the differentially methylated genes. The results suggest that multiple GPCRs and their ligands are regulated through methylation and correlated with patient survival, providing opportunities for better treatment strategies for NETs based on molecular features.
SCIENTIFIC REPORTS
(2021)
Review
Cell Biology
Tanya N. Soliman, Daniel Keifenheim, Peter J. Parker, Duncan J. Clarke
Summary: This article integrates recent molecular discoveries to gain insights into Topoisomerase IIA checkpoints and discusses how cells regulate cell cycle progression for faithful genome transmission. Understanding these mechanisms is crucial for developing potential therapies for diseases such as cancer.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Huanhuan Ren, Kaixian Wang, Zirui Liu, Xuansheng Zhong, Meng Liang, Yaping Liao
Summary: Folate deficiency is associated with male subfertility and impaired spermatogenesis. This study established an animal model of folate deficiency and found that it leads to decreased sperm counts and increased defects in sperm head. Folate deficiency also induces chromosomal instability and dysfunction of the spindle assembly checkpoint.
DNA AND CELL BIOLOGY
(2023)
Article
Oncology
Takanori Matsuura, Yoshihide Ueda, Yoshiyuki Harada, Kazuki Hayashi, Kisara Horisaka, Yoshihiko Yano, Shinichi So, Masahiro Kido, Takumi Fukumoto, Yuzo Kodama, Eiji Hara, Tomonori Matsumoto
Summary: By evaluating chromosome duplication, we found that 36% of HCCs have polyploidy, which is considered as an aggressive and poor prognosis subgroup. Through transcriptome analysis and histological examination, we identified distinctive cellular morphology and architecture in polyploid HCCs, and overexpression of specific markers can efficiently predict prognosis.
BRITISH JOURNAL OF CANCER
(2023)
Article
Multidisciplinary Sciences
Emmanuel K. Teye, Shasha Lu, Fangyuan Chen, Wenrui Yang, Thomas Abraham, Douglas B. Stairs, Gregory S. Yochum, Robert A. Brodsky, Jefrey J. Pu
Summary: PIGN, as a regulator of the spindle assembly checkpoint, affects the activation of mitotic checkpoint in leukemic cells, which in turn influences chromosome segregation, suggesting a crucial role in suppressing chromosomal instability associated with leukemia.
SCIENTIFIC REPORTS
(2021)
Review
Oncology
Pia Puzar Dominkus, Petra Hudler
Summary: The mutational signatures found in gastric tumors can be used as prognostic biomarkers and provide new information about the drivers of gastric carcinogenesis, which might be useful for the improvement in disease treatment options.
Article
Chemistry, Medicinal
Jibu Lu, Yongjun Huang, Jing Huang, Rui He, Minhao Huang, Xiaoyun Lu, Yong Xu, Fengtao Zhou, Zhang Zhang, Ke Ding
Summary: The first examples of threonine tyrosine kinase (TTK) PROTACs were successfully designed and synthesized, showing strong degradation effects in human colorectal cancer cells and potential anticancer activities.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Cerys E. Currie, Emma Ford, Lucy Benham Whyte, Deborah M. Taylor, Bettina P. Mihalas, Muriel Erent, Adele L. Marston, Geraldine M. Hartshorne, Andrew D. McAinsh
Summary: This study reveals that errors in chromosome segregation during the first mitotic division of human embryos can be tolerated and uncovers the cell biological events that contribute to preimplantation mosaicism.
NATURE COMMUNICATIONS
(2022)