Article
Biochemistry & Molecular Biology
Bin Guo, Xiaorui Shi, Zhe Ma, Moxuan Ji, Chu Tang, Fu Wang
Summary: A genetically engineered ratiometric dual luciferase reporter has been developed to continuously quantify changes in mRNA splice variants in vivo. This reporter system minimizes the influence of indirect factors on splicing within the same individual, with the ratio of two luciferase intensities representing the dynamic splicing efficiency of pre-mRNA. This tool offers a convenient and robust method for screening and identifying small molecules or trans-acting factors affecting specific splicing reactions.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Editorial Material
Oncology
Dalibor Blazek
Summary: Human cyclin-dependent kinases (CDKs) play a crucial role in regulating the cell cycle and transcription. Despite their involvement in basic cellular processes, CDKs are often dysregulated in tumors and are promising targets for cancer therapy. CDK11, an essential gene for the growth of many malignancies, has previously had an unclear cellular function, and the mode-of-action of the first CDK11 inhibitor, OTS964, was unknown. However, recent research has shown that OTS964 prevents spliceosome activation, revealing CDK11's key role in pre-mRNA splicing regulation. This study discusses the therapeutic potential of CDK11 in cancer treatment.
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Asmaa Samy, Mehmet Kemal Ozdemir, Reda Alhajj
Summary: This study focuses on the relationship between SF3B1 and four types of cancer (MDS, AML, CLL, and BC). The results show that SF3B1 is more closely associated with hematologic malignancies (MDS, AML, CLL) than with breast cancer (BC). Different gene networks may be required to investigate the impact of mutant splicing factors on cancer development based on the type of cancer. Additionally, we summarized the set of genes and cellular pathways that are affected by aberrant splicing in cancerous cells based on the literature analyzed in this study.
SCIENTIFIC REPORTS
(2023)
Article
Chemistry, Physical
Angelo Spinello, Pavel Janos, Riccardo Rozza, Alessandra Magistrato
Summary: The key to accurate pre-mRNA splicing is the recognition of intronic sequences by specific splicing factors. The splicing factor 3b (SF3b) recognizes the branchpoint sequence (BPS), which is crucial for splice site selection. Mutations in SF3B1, including the most common K700E mutation, lead to aberrant splicing and are associated with hematologic malignancies. This study combines molecular dynamics simulations and dynamical network theory analysis to understand how SF3B mutations affect pre-mRNA selection. The findings suggest that the mutated SF3B1 disrupts RNA-mediated allosteric cross-talk between the BPS and the mutation site, contributing to cancer-associated missplicing. This study enhances our understanding of pre-mRNA metabolism in eukaryotes.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
Article
Multidisciplinary Sciences
Jian Zhang, Ji Huang, Ke Xu, Peiqi Xing, Yue Huang, Zhaoqi Liu, Liang Tong, James L. Manley
Summary: SF3B1 is the most frequently mutated spliceosomal gene in cancer. A study identifies DHX15 as the critical helicase that functions with SUGP1 to cause the splicing defects of mutant SF3B1 in cancer.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Cell Biology
Hui Yang, Bruce Beutler, Duanwu Zhang
Summary: The spliceosome, while crucial for cell function, can also be implicated in diseases and serve as a target for cancer therapy. Research has shown connections between the spliceosome and immune signaling, leading to immune dysregulation. Furthermore, core spliceosome components have splicing-independent immune functions, adding to their functional diversity.
Article
Neurosciences
Simon Chamberland, Erica R. Nebet, Manuel Valero, Monica Hanani, Robert Egger, Samantha B. Larsen, Katherine W. Eyring, Gyorgy Buzsaki, Richard W. Tsien
Summary: The firing of hippocampal fast-spiking parvalbumin-expressing interneurons can be persistently interrupted for several hundred milliseconds following brief inhibition, maintaining the cells in a depolarized, quiescent state through a cell-autonomous mechanism. This persistent interruption favors spike generation in pyramidal cells, impacting micro-circuit function.
Article
Multidisciplinary Sciences
Rhys Green, Mark Taggart, Deborah Pain, Keturah Smithson
Summary: Carcasses of pheasants killed by hunters using lead shotgun ammunition sold in the UK contain small lead fragments that are difficult for consumers to detect and remove, potentially exposing them to elevated levels of dietary lead.
Review
Oncology
Manuel D. Gahete, Natalia Herman-Sanchez, Antonio C. Fuentes-Fayos, Juan L. Lopez-Canovas, Raul M. Luque
Summary: The dysregulation of the splicing process in breast cancer leads to the generation and functional changes of oncogenic splicing variants, increasing the malignancy of the cancer and resistance to treatment.
ENDOCRINE-RELATED CANCER
(2022)
Review
Oncology
Carlos A. Nino, Rossella Scotto di Perrotolo, Simona Polo
Summary: This review summarizes the cancer hotspot mutations in spliceosome components, focusing on the effects of mutations in U1 snRNA, SF3B1, and U2AF1 on splice site selection and cancer development.
Review
Oncology
Claudio Sette, Maria Paola Paronetto
Summary: High throughput exome sequencing has revealed recurrent cancer-associated mutations in spliceosomal components, which promote tumor phenotype and make cancer cells vulnerable to splicing-targeting approaches. Thus, understanding the mechanisms and roles of abnormal splicing in tumor metabolism could lead to the development of novel tumor-targeting drugs.
Article
Multidisciplinary Sciences
Leo Bellin, Francisco Del Cano-Ochoa, Adrian Velazquez-Campoy, Torsten Moehlmann, Santiago Ramon-Maiques
Summary: ATC in plants is regulated by feedback inhibition via UMP, which binds to a plant-specific loop and blocks the active site, competing with substrate binding. This unique regulatory mechanism of plant ATCs could be utilized to modulate de novo pyrimidine synthesis and plant growth.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Yingwei Li, Zhongshao Chen, Jiali Peng, Cunzhong Yuan, Shi Yan, Ning Yang, Peng Li, Beihua Kong
Summary: This study found that SNRPB plays a key role in ovarian cancer and is associated with poor prognosis. Functionally, SNRPB knockdown inhibits ovarian cancer cell proliferation and invasion, while overexpression has the opposite effect. SNRPB expression increases after cisplatin treatment, and silencing SNRPB enhances ovarian cancer cell sensitivity to cisplatin. SNRPB promotes ovarian cancer progression by repressing exon 3 skipping of POLA1 and BRCA2.
Article
Biochemistry & Molecular Biology
Anke Augspach, Kyle D. Drake, Luca Roma, Ellen Qian, Se Ri Lee, Declan Clarke, Sushant Kumar, Muriel Jaquet, John Gallon, Marco Bolis, Joanna Triscott, Jose A. Galvan, Yu Chen, George N. Thalmann, Marianna Kruithof-de Julio, Jean-Philippe P. Theurillat, Stefan Wuchty, Mark Gerstein, Salvatore Piscuoglio, Rahul N. Kanadia, Mark A. Rubin
Summary: The evolutionarily conserved minor spliceosome (MiS) is essential for the expression of -714 minor intron-containing genes (MIGs) involved in important cellular processes. In prostate cancer (PCa), MiS activity is regulated by androgen receptor signaling and elevated levels of U6atac. Inhibition of MiS through siU6atac disrupts minor intron splicing and has a potent effect on inhibiting tumor growth, especially in advanced therapy-resistant PCa. MiS is identified as a vulnerability in lethal PCa and potentially other cancers.
Article
Biology
Mark C. Johnson, Geylani Can, Miguel Monteiro Santos, Diana Alexander, Philip Zegerman
Summary: This study reveals that Rad53 phosphorylates the same substrates throughout the cell cycle, not just in S-phase, suggesting its roles beyond S-phase. By inhibiting 51d3 and Dbf4, Rad53 limits re-replication in G2/M, preventing gene amplification, and inhibiting these substrates in G1 prevents premature initiation at the G1/S transition. This redefinition of the 'S-phase checkpoint' has implications for understanding checkpoint function in cancers without proper cell cycle controls.
