Article
Biology
Ryota Miyashita, Atsuya Nishiyama, Weihua Qin, Yoshie Chiba, Satomi Kori, Norie Kato, Chieko Konishi, Soichiro Kumamoto, Hiroko Kozuka-Hata, Masaaki Oyama, Yoshitaka Kawasoe, Toshiki Tsurimoto, Tatsuro S. Takahashi, Heinrich Leonhardt, Kyohei Arita, Makoto Nakanishi
Summary: The ubiquitin signaling pathway dependent on UHRF1 plays a crucial role in the regulation of maintenance DNA methylation. This study reveals the mechanisms of PAF15 removal from chromatin through deubiquitylation by USP7 and unloading by ATAD5. It also demonstrates the importance of completion of maintenance DNA methylation for the termination of UHRF1-mediated ubiquitin signaling.
Article
Oncology
Tanveer Ahmad, Waseem Ashraf, Abdulkhaleg Ibrahim, Liliyana Zaayter, Christian D. Muller, Ali Hamiche, Yves Mely, Christian Bronner, Marc Mousli
Summary: TIP60 plays a tumor suppressor role by regulating UHRF1 expression, decreasing levels of UHRF1 and DNMT1, disrupting the USP7-UHRF1 association, inducing the degradation of UHRF1 in an auto-ubiquitination-dependent manner, and activating the p73-mediated apoptotic pathway.
INTERNATIONAL JOURNAL OF ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Barbara Ben Yamin, Sana Ahmed-Seghir, Junya Tomida, Emmanuelle Despras, Caroline Pouvelle, Andrey Yurchenko, Jordane Goulas, Raphael Corre, Quentin Delacour, Nathalie Droin, Philippe Dessen, Didier Goidin, Sabine S. Lange, Sarita Bhetawal, Maria Teresa Mitjavila-Garcia, Giuseppe Baldacci, Sergey Nikolaev, Jean Charles Cadoret, Richard D. Wood, Patricia L. Kannouche
Summary: The study highlights the crucial role of DNA polymerase zeta in bypassing DNA damage and cell proliferation, as well as the significance of REV3L's interactions with heterochromatin components in maintaining chromosome stability.
Editorial Material
Biochemistry & Molecular Biology
Janardan N. Gavade, Ben E. Black
Summary: A new study reveals that the efficiency of new centromere formation is dictated by subnuclear location.
Article
Oncology
Yongming Fu, Tuoyu Cao, Xiaorui Zou, Yubing Ye, Youhong Liu, Yuchong Peng, Tanggang Deng, Linglong Yin, Xiong Li
Summary: The activation of PI3K/AKT signaling pathway and epigenetic aberrations are important characteristics of castration-resistant prostate cancer (CRPC). In this study, the regulatory mechanism of AKT1 on UHRF1 was investigated, and the anticancer efficacy of the AKT phosphorylation inhibitor MK2206 in combination with abiraterone was validated both in vitro and in vivo. The findings demonstrated that AKT1 directly phosphorylates UHRF1, leading to its degradation and affecting its interactions with USP7 and BTRC. MK2206 significantly enhanced the sensitivity of abiraterone-refractory prostate cancer cells and xenografts to abiraterone by decreasing UHRF1 protein level and inducing cellular senescence and apoptosis. This study provides a new molecular mechanism of abiraterone resistance and a potential therapeutic approach for PCa patients by targeting the PI3K/AKT1 pathway.
Article
Cell Biology
Manuel Guthmann, Chen Qian, Irene Gialdini, Tsunetoshi Nakatani, Andreas Ettinger, Tamas Schauer, Igor Kukhtevich, Robert Schneider, Don C. Lamb, Adam Burton, Maria-Elena Torres-Padilla
Summary: In this study, Guthmann et al. demonstrate that pericentromeric heterochromatin undergoes phase separation and transition during early embryonic development in mice. They also show that weak hydrophobic interactions and ATRX recruitment influence the biophysical properties of heterochromatin and chromocenter maturation. These findings provide new insights into the self-organization of chromatin domains during mammalian embryogenesis.
GENES & DEVELOPMENT
(2023)
Review
Microbiology
Benoit Arcangioli, Serge Gangloff
Summary: This article describes how Schizosaccharomyces pombe, a variant of the budding yeast, relies on efficient genetic sex determination and alternating haploid/diploid phases to achieve high reproductive efficiency in response to environmental conditions. By exploring the mating-type switching process and the interaction between genetics and epigenetics, it underscores the significance of basic research in gaining a better understanding of chromatin biology.
MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Peng Xu, Lan Zhang, Yao Xiao, Wei Li, Zhiqiang Hu, Rukui Zhang, Jin Li, Feizhen Wu, Yanping Xi, Qingping Zou, Zhentian Wang, Rui Guo, Honghui Ma, Shihua Dong, Min Xiao, Zhicong Yang, Xiaoguang Ren, Chaochun Wei, Wenqiang Yu
Summary: The well-established functions of UHRF1 in DNA biological processes have been expanded to show that UHRF1 also plays a role in RNA metabolism by regulating alternative RNA splicing. The interaction of UHRF1 with various splicing factors and its involvement in U snRNAs suggest a complex mechanism at play, providing insights into UHRF1-mediated alternative RNA splicing and its implications in disease development.
HUMAN MOLECULAR GENETICS
(2021)
Article
Biology
Po-Jen Wu, Shian-Jang Yan
Summary: HP1a-mediated heterochromatin formation in the fat body promotes antimicrobial responses by epigenetically upregulating antimicrobial peptides of the imd pathway in Drosophila melanogaster.
Article
Biochemistry & Molecular Biology
Aushaq B. Malla, Haoming Yu, Delaney Farris, Srilekha Kadimi, TuKiet T. Lam, Andy L. Cox, Zachary D. Smith, Bluma J. Lesch
Summary: This study reveals that DOT1L plays a crucial role in maintaining pericentromeric heterochromatin and genome stability. By regulating the methylation of H3K79, DOT1L is involved in the transcription of repetitive satellite sequences, thereby stabilizing heterochromatin structures and ensuring preimplantation viability.
Article
Multidisciplinary Sciences
Maxime M. C. Tortoraa, Lucy D. Brennan, Gary Karpen, Daniel Jost
Summary: A minimal theoretical framework is used to investigate the interaction between HP1 and chromatin polymer, revealing that the specific affinity of HP1 for H3K9me2/3 promotes the formation of stable PCH condensates in the nucleus.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Cell Biology
Melina Vaurs, Karel Naiman, Chainez Bouabboune, Sudhir Rai, Katarzyna Ptasinska, Marion Rives, Samah Matmati, Antony M. Carr, Vincent Geli, Stephane Coulon
Summary: Efficient replication of terminal DNA is important for telomere stability. In fission yeast, the Stn1-Ten1 complex is crucial for replication of a subtelomeric region called STE3-2, and its function relies on its association with shelterin proteins. When Stn1-Ten1 function is compromised, a homologous recombination-based fork restart mechanism becomes necessary for STE3-2 stability. The firing of an origin normally inhibited by Rif1 can bypass the replication defect of subtelomeres.
Article
Biology
Serge Bauwens, Liudmyla Lototska, Stephane Koundrioukoff, Michelle Debatisse, Jing Ye, Eric Gilson, Aaron Mendez-Bermudez
Summary: The study revealed that TRF2 plays a crucial role in pericentromeric heterochromatin replication by regulating both replication initiation and elongation, impacting the replication activity of pericentromeric DNA.
Review
Genetics & Heredity
Evon M. DeBose-Scarlett, Beth A. Sullivan
Summary: Centromeres are crucial for genome inheritance, with abnormal function linked to various diseases. Ectopic centromeres can form at new genomic locations, impacting genome stability and disease development. While certain genome regions influence neocentromere activation, the universal mechanism remains unclear.
ANNUAL REVIEW OF GENETICS, VOL 55
(2021)
Article
Biochemistry & Molecular Biology
Manasi S. Apte, Hirohisa Masuda, David Lee Wheeler, Julia Promisel Cooper
Summary: The formation of HAATI(rDNA) is initiated and limited by a single translocation that brings rDNA from Chromosome III to subtelomeric elements on Chromosome I or II. This unique translocation creates a STE-rDNA junction that is efficiently copied to other chromosome ends, independent of RNAi or Ino80C. RNAi and Ino80C play dual roles in promoting the formation of HAATI(rDNA) as part of their canonical machineries, but also inhibit the formation of the rare HAATI(STE) in non-canonical, pathway-independent ways. This study reveals an unexpected crosstalk between RNAi and Ino80C in controlling unusual translocation reactions that establish telomere-free linear chromosome ends.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Critical Care Medicine
David A. Harrison, Ben C. Creagh-Brown, Kathryn M. Rowan
Summary: Persistent critical illness is a common clinical syndrome in the ICU, which is associated with increased healthcare utilization and adverse outcomes. This study aimed to assess the predictive factors for survival in patients with persistent critical illness and compare the characteristics and outcomes of these patients with others. The findings suggest the need for improved understanding of long-term outcomes and the development of tools for prognostication.
JOURNAL OF THE INTENSIVE CARE SOCIETY
(2023)
Article
Critical Care Medicine
Robert Darnell, Christopher Newell, Julia Edwards, Emma Gendall, David Harrison, Stefan Sprinckmoller, Paul Mouncey, Doug Gould, Matt Thomas
JOURNAL OF THE INTENSIVE CARE SOCIETY
(2023)
Article
Oncology
Jennifer Bre, Alison L. Dickson, Oliver J. Read, Ying Zhang, Fiona G. McKissock, Peter Mullen, Peijun Tang, Greice M. Zickuhr, Clarissa M. Czekster, David J. Harrison
Summary: NUC-3373 is a modified version of 5-fluorodeoxyuridine that shows higher anti-cancer activity and better safety profile compared to 5-FU, overcoming its limitations and pharmacologic challenges in clinical use.
CANCER CHEMOTHERAPY AND PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Christina Fell, Mahnaz Mohammadi, David Morrison, Ognjen Arandjelovic, Sheeba Syed, Prakash Konanahalli, Sarah Bell, Gareth Bryson, David J. Harrison, David Harris-Birtill
Summary: In this study, AI was used to categorise endometrial biopsy whole slide images into malignant, other, benign, or insufficient categories. The digitalisation of pathology has led to the automation of image analysis, and a model that can classify slides in this way would help prioritise pathologists' workload and reduce diagnosis time for cancer patients. The final model achieved an accuracy of 90% in classifying slides correctly and 97% in the malignant class, demonstrating its effectiveness in assisting pathologists.
Article
Oncology
Georges Bedran, Hans-Christof Gasser, Kenneth Weke, Tongjie Wang, Dominika Bedran, Alexander Laird, Christophe Battail, Fabio Massimo Zanzotto, Catia Pesquita, Hakan Axelson, Ajitha Rajan, David J. Harrison, Aleksander Palkowski, Maciej Pawlik, Maciej Parys, Robert O'Neill, Paul M. Brennan, Stefan N. Symeonides, David R. Goodlett, Kevin Litchfield, Robin Fahraeus, Ted R. Hupp, Sachin Kote, Javier A. Alfaro
Summary: Using deep learning mass spectrometry, we developed a proteogenomic pipeline to discover noncanonical MHC class I-associated peptides (ncMAP) from noncoding regions. Analyzing data from 26 MHC class I immunopeptidomic studies across 11 different cancer types, we identified an atlas of 8,601 ncMAPs and suggested 17 cancer-selective ncMAPs as attractive therapeutic targets.
CANCER IMMUNOLOGY RESEARCH
(2023)
Article
Computer Science, Information Systems
Georg Wolflein, In Hwa Um, David J. Harrison, Ognjen Arandjelovic
Summary: In recent years, efforts have been made to digitize whole-slide images of cancer tissue, providing new opportunities for deep learning in oncology. One promising application is virtual staining, where a deep learning model reproduces the appearance of stained tissue sections based on different input stains. However, there is a scarcity of supervised training data with aligned input and output stains on the same tissue sections. In this work, a dataset of ten whole-slide images of clear cell renal cell carcinoma tissue sections, along with over 600,000 patches and cell segmentation masks, is introduced to facilitate the development of deep learning methods for digital pathology and benchmark virtual staining models.
Article
Biochemistry & Molecular Biology
Suneeta Devi, Anna E. Carberry, Greice M. Zickuhr, Alison L. Dickson, David J. Harrison, Rafael G. da Silva
Summary: DNPH1 catalyzes the N-ribosidic bond cleavage of 5-hydroxymethyl-2'-deoxyuridine 5'-monophosphate to generate 2-deoxyribose 5-phosphate and 5-hydroxymethyluracil. The crystal structures of unliganded DNPH1 and DNPH1 bound with 2'-deoxyuridine 5'-monophosphate were solved, revealing the interaction between the catalytic Glu residue and a conserved Tyr residue. Functional data supported the proposed mechanism, with hydrolysis of dUMP confirmed by liquid chromatography-mass spectrometry analysis. The pH-rate profile and solvent isotope effects provided insights into the catalytic mechanism.
Article
Multidisciplinary Sciences
Xiangdong Lv, Xuan Lu, Jin Cao, Qin Luo, Yao Ding, Fanglue Peng, Apar Pataer, Dong Lu, Dong Han, Eric Malmberg, Doug W. Chan, Xiaoran Wang, Sara R. Savage, Sufeng Mao, Jingjing Yu, Fei Peng, Liang Yan, Huan Meng, Laure Maneix, Yumin Han, Yiwen Chen, Wantong Yao, Eric C. Chang, Andre Catic, Xia Lin, George Miles, Pengxiang Huang, Zheng Sun, Bryan Burt, Huamin Wang, Jin Wang, Qizhi Cathy Yao, Bing Zhang, Jack A. Roth, Bert W. O'Malley, Matthew J. Ellis, Mothaffar F. Rimawi, Haoqiang Ying, Xi Chen
Summary: Proteostasis reprogramming is identified as a key convergence point of multiple mechanisms of resistance to mutant KRAS inhibitors. The reactivation of IRE1a, in an ER stress-independent manner, restores proteostasis in acquired KRAS inhibitor-resistant tumors. IRE1a phosphorylation and stability are promoted by reactivated ERK and hyperactivated AKT, which can be overcome by suppressing IRE1a.
Article
Cell Biology
Mustafa Elshani, In Hwa Um, Steve Leung, Paul A. Reynolds, Alex Chapman, Mary Kudsy, David J. Harrison
Summary: This study investigates the expression of NFE2L1 in podocytes and its correlation with kidney disease. The results show that NFE2L1 expression is decreased in renal diseases, and its nuclear expression is reduced under PAN treatment.
Article
Computer Science, Artificial Intelligence
Clarisse F. de Vries, Samantha J. Colosimo, Roger T. Staff, Jaroslaw A. Dymiter, Joseph Yearsley, Deirdre Dinneen, Moragh Boyle, David J. Harrison, Lesley A. Anderson, Gerald Lip
Summary: Artificial intelligence (AI) tools may be helpful in breast screening mammography programs, but their generalizability to new settings should be validated. This study assessed the performance of a commercially available breast screening AI algorithm in a specific clinical site using a 3-year dataset. The algorithm's recall rates were high initially but reduced after threshold calibration and were influenced by software upgrades. Validating AI performance and thresholds in new clinical settings is important, and quality assurance systems should ensure consistency.
RADIOLOGY-ARTIFICIAL INTELLIGENCE
(2023)
Proceedings Paper
Computer Science, Artificial Intelligence
Georg Wolflein, In Hwa Um, David J. Harrison, Ognjen Arandjelovic
Summary: Understanding the presence and density of specific immune cell types is crucial for evaluating a patient's immune response to cancer. However, traditional immunofluorescence staining methods for identifying T cell subtypes are costly, time-consuming, and not commonly used in clinical settings. In this study, we propose a framework that utilizes generative adversarial networks to virtually stain Hoechst images with CD3 and CD8 markers, enabling the identification of T cell subtypes in clear cell renal cell carcinoma. By jointly learning both staining tasks, our method incorporates mutually beneficial information to improve accuracy. We also introduce a novel metric to evaluate the quality of virtual staining.
2023 IEEE/CVF WINTER CONFERENCE ON APPLICATIONS OF COMPUTER VISION (WACV)
(2023)
