Article
Multidisciplinary Sciences
Sara Priego Moreno, Javier Miralles Fuste, Melanie Kaiser, Julia Su Zhou Li, Joe Nassour, Candy Haggblom, Eros Lazzerini Denchi, Jan Karlseder
Summary: The appropriate regulation of telomere length homeostasis is crucial for genome integrity. The telomere-binding protein TZAP has been suggested to regulate telomere length through telomere trimming, but the molecular mechanisms are not understood. In this study, we found that TZAP can efficiently bind to telomeres in the absence of ATRX/DAXX and induce telomere dysfunction and ALT-like activity, resulting in the generation of t-circles and c-circles in a BTR-dependent manner.
Article
Biochemistry & Molecular Biology
Maheshi Udugama, Benjamin Vinod, F. Lyn Chan, Linda Hii, Andrew Garvie, Philippe Collas, Paul Kalitsis, David Steer, Partha P. Das, Pratibha Tripathi, Jeffrey R. Mann, Hsiao P. J. Voon, Lee H. Wong
Summary: In this study, researchers found that the phosphorylation of H3.3 at the S31 residue regulates heterochromatin accessibility at telomeres during replication. This process is achieved through the regulation of the histone demethylase KDM4B. Abnormal phosphorylation of H3.3 S31 can lead to altered H3K9me3 modification and subsequent DNA damage. The regulation of H3.3 S31Ph also affects the overall chromatin integrity of other heterochromatin regions.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Lia M. Pinto, Alexandros Pailas, Max Bondarchenko, Abhishek Bharadwaj Sharma, Katrin Neumann, Anthony J. Rizzo, Celine Jeanty, Nathalie Nicot, Carine Racca, Mindy K. Graham, Catherine Naughton, Yaqun Liu, Chun-Long Chen, Paul J. Meakin, Nick Gilbert, Sebastien Britton, Alan K. Meeker, Christopher M. Heaphy, Florence Larminat, Eric Van Dyck
Summary: Maintaining chromatin integrity at centromeres is crucial for preventing DNA breaks and genomic instability. The histone chaperone complex ATRX/DAXX is involved in establishing and maintaining centromeric chromatin structure. We discovered a novel ATRX-independent function for DAXX in promoting genome stability by preventing R-loop accumulation and DNA double-strand break formation at centromeres.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Pathology
Jacqueline A. Brosnan-Cashman, Christine M. Davis, Bill H. Diplas, Alan K. Meeker, Fausto J. Rodriguez, Christopher M. Heaphy
Summary: The study found that a subset of giant cell GBM utilizes the ALT telomere maintenance mechanism, and in addition to ATRX loss, tumors with SMARCAL1 alterations are prevalent in giant cell GBM.
Review
Biochemistry & Molecular Biology
Kazumasa Yoshida, Masatoshi Fujita
Summary: During genome duplication, eukaryotic cells may encounter various replication stresses that can lead to chromosome breaks, genomic instability, and tumor development if not properly resolved. To prevent these consequences, cells have mechanisms in place to enhance the resilience of replication machineries against replication stresses.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Cell Biology
Anaid Benitez, Marie Sebald, Radhakrishnan Kanagaraj, Monica C. Rodrigo-Brenni, Ying Wai Chan, Chih-Chao Liang, Stephen C. West
Summary: Our genomes contain common fragile sites (CFSs), which are difficult to replicate and cause genomic instability. Loss of GEN1, an endonuclease, reduces CFS expression, leading to defects in DNA synthesis, chromosome segregation, and DNA damage. This suggests that GEN1 plays a dual role in resolving both DNA replication and recombination intermediates.
Article
Biochemistry & Molecular Biology
Hee Jin Chung, Joo Rak Lee, Tae Moon Kim, Soomi Kim, Kibeom Park, Myung-Jin Kim, Eunyoung Jung, Subin Kim, Eun A. Lee, Jae Sun Rae, Sunyoung Hwang, Ja Yil Lee, Orlando D. Scharer, Yonghwan Kim, Kyungjae Myung, Hongtae Kim
Summary: In this study, ZNF212 is identified as a new binding partner for TRAIP and is found to colocalize with sites of DNA damage. Depletion of ZNF212 causes defects in the DDR and HR-mediated repair, and acts upstream of the Neil3 and Fanconi anemia pathways in ICL repair. Furthermore, ZNF212 interacts with NEIL3 and promotes its recruitment to ICL lesions.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Clinical Neurology
Stella G. Cavalcante, Benedito J. A. Pereira, Antonio M. Lerario, Paula R. Sola, Sueli M. Oba-Shinjo, Suely K. N. Marie
Summary: The ATRX-DAXX-H3.3 chromatin remodeler complex is associated with telomere dysfunction and tumor progression in different types of cancer, with ATRX upregulation observed in grade II/III meningiomas. Telomere length in meningiomas shows low variability across different ages and malignant grades, in contrast to the shortening observed in normal controls with aging.
CLINICAL NEUROLOGY AND NEUROSURGERY
(2021)
Article
Cell Biology
Isabelle Trier, Elizabeth M. Black, Yoon Ki Joo, Lilian Kabeche
Summary: We have found that ATR kinase, a master regulator of the DNA damage response, protects CENP-A protein occupancy at centromeres during interphase independent of DNA damage. Furthermore, ATR-dependent phosphorylation of DAXX protein regulates CENP-A occupancy at centromeres and DAXX localization. Lastly, acute ATR inhibition during interphase leads to kinetochore formation defects and an increased rate of lagging chromosomes. These findings highlight a mechanism by which ATR protects centromere identity and genome stability.
Article
Oncology
Jemina Lehto, Anna Huguet Ninou, Dimitrios Chioureas, Jos Jonkers, Nina M. S. Gustafsson
Summary: Chemotherapeutics that introduce DNA crosslinks, like platinum drugs, are used to treat cancers but face limitations due to side effects and acquired resistance. Targeting DNA repair, particularly the interaction between CX3CR1 and the FA repair pathway, holds promise in improving treatment responses and reducing side effects.
Article
Multidisciplinary Sciences
Marta Barrientos-Moreno, Douglas Maya-Miles, Marina Murillo-Pineda, Sara Fontalva, Monica Perez-Alegre, Eloisa Andujar, Felix Prado
Summary: Genome duplication occurs through the coordinated action of DNA replication and nucleosome assembly. Defective nucleosome assembly causes DNA lesions and loss of chromatin integrity, which can be restored. The mechanism of chromatin restoration is unknown.
SCIENTIFIC REPORTS
(2023)
Article
Cell Biology
Valeria Dolce, Sabrina Dusi, Michele Giannattasio, Chinnu Rose Joseph, Marco Fumasoni, Dana Branzei
Summary: In this study, the connections between Ctf4-mediated processes involved in drug resistance were investigated by conducting a suppressor screen of ctf4 Delta sensitivity to the methylating agent MMS. The findings demonstrate a chromatin-based drug resistance mechanism in which defects in parental histone transfer after replication fork passage impair error-free recombination bypass and lead to up-regulation of TLS-mediated mutagenesis and drug resistance.
GENES & DEVELOPMENT
(2022)
Article
Biochemistry & Molecular Biology
Shuailin Hao, Ya Wang, Yuqin Zhao, Wen Gao, Wei Cui, Youhang Li, Jian Cui, Yu Liu, Lixiu Lin, Xingzhi Xu, Hailong Wang
Summary: Protein reversible post-translational modification (PTM) plays a crucial role in cellular processes. Lysine crotonylation (Kcr), a newly identified PTM, is found to be involved in replication stress response. The modification of histone H2A at lysine 119 (H2AK119) by crotonylation and ubiquitination specifically regulates transcription-replication conflicts (TRCs), protecting genome stability under replication stress.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Matthew Nolan, Kenneth Knudson, Marina K. Holz, Indrajit Chaudhury
Summary: mTOR interacts and cooperates with FANCD2 during replication stress to provide cellular stability, mediate stalled replication fork restart, and prevent nucleolytic degradation of the nascent DNA strands. This study reveals a novel functional cross-talk between the mTOR and FA DNA repair pathways to ensure genomic stability.
Article
Multidisciplinary Sciences
Yajuan Yang, Weiwei Xu, Fei Gao, Canxin Wen, Simin Zhao, Yongze Yu, Wenlin Jiao, Xin Mi, Yingying Qin, Zi-Jiang Chen, Shidou Zhao
Summary: This study reveals that mouse PGCs experience a high frequency of transcription-replication conflicts, leading to replication stress and DNA damage. The FA pathway is found to play a crucial role in PGC proliferation, and disabling this pathway results in severe cell loss and sterility.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Susanna Stroik, Kevin Kurtz, Kevin Lin, Sergey Karachenets, Chad L. Myers, Anja-Katrin Bielinsky, Eric A. Hendrickson
NUCLEIC ACIDS RESEARCH
(2020)
Article
Multidisciplinary Sciences
Tanay Thakar, Wendy Leung, Claudia M. Nicolae, Kristen E. Clements, Binghui Shen, Anja-Katrin Bielinsky, George-Lucian Moldovan
NATURE COMMUNICATIONS
(2020)
Article
Hematology
Yusuke Okamoto, Masako Abe, Anfeng Mu, Yasuko Tempaku, Colette B. Rogers, Ayako L. Mochizuki, Yoko Katsuki, Masato T. Kanemaki, Akifumi Takaori-Kondo, Alexandra Sobeck, Anja-Katrin Bielinsky, Minoru Takata
Summary: Fanconi anemia (FA) is a hereditary disorder caused by mutations in any 1 of 22 FA genes. Recent studies have shown that the DNA/RNA helicase SLFN11 plays a role in cell death sensitivity to chemotherapeutic treatments in cancer cells. The depletion of SLFN11 has been shown to improve cell survival in FA patient-derived cells, suggesting a potential link between SLFN11 and FA pathophysiology.
Article
Medicine, Research & Experimental
Emily M. Mace, Silke Paust, Matilde I. Conte, Ryan M. Baxley, Megan M. Schmit, Sagar L. Patil, Nicole C. Guilz, Malini Mukherjee, Ashley E. Pezzi, Jolanta Chmielowiec, Swetha Tatineni, Ivan K. Chinn, Zeynep Coban Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Asbjorg Stray-Pedersen, Rachel E. Bradley, Mo Moody, Philip P. Connor, Adrian G. Heaps, Colin Steward, Pinaki P. Banerjee, Richard A. Gibbs, Malgorzata Borowiak, James R. Lupski, Stephen Jolles, Anja K. Bielinsky, Jordan S. Orange
JOURNAL OF CLINICAL INVESTIGATION
(2020)
Article
Biochemistry & Molecular Biology
Maya Raghunandan, Dan Geelen, Eva Majerova, Anabelle Decottignies
Summary: The study reveals an interference between telomerase and ALT pathways in some cancer cells, with hTR and NHP2 playing crucial roles in DDR regulation at ALT telomeres.
Article
Multidisciplinary Sciences
Ryan M. Baxley, Wendy Leung, Megan M. Schmit, Jacob Peter Matson, Lulu Yin, Marissa K. Oram, Liangjun Wang, John Taylor, Jack Hedberg, Colette B. Rogers, Adam J. Harvey, Debashree Basu, Jenny C. Taylor, Alistair T. Pagnamenta, Helene Dreau, Jude Craft, Elizabeth Ormondroyd, Hugh Watkins, Eric A. Hendrickson, Emily M. Mace, Jordan S. Orange, Hideki Aihara, Grant S. Stewart, Edward Blair, Jeanette Gowen Cook, Anja-Katrin Bielinsky
Summary: MCM10 deficiency results in chronic replication stress, reducing cell viability due to increased genomic instability and telomere erosion. Loss of MCM10 function constrains telomerase activity, potentially leading to a build-up of abnormal replication structures and terminally-arrested replication forks that require processing by MUS81.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Maya Raghunandan, Anabelle Decottignies
Summary: Human telomerase has been found to have multifaceted functions beyond telomeric repeat synthesis. Both hTERT and hTR play roles in cellular pathways to enhance cell fitness and protection against apoptosis. The non-canonical functions of hTR, such as regulating replication protein A at telomeres, may be relevant in normal somatic cells that naturally silence the hTERT gene but maintain hTR expression.
Review
Biochemistry & Molecular Biology
Ya-Chu Chang, Marissa K. Oram, Anja-Katrin Bielinsky
Summary: This passage describes the functions and mechanisms of Small Ubiquitin-like Modifier (SUMO)-targeted E3 Ubiquitin Ligases (STUbLs), including their roles in cell cycle regulation, DNA repair, replication, mitosis, and transcription, as well as the importance of maintaining genome stability across different species.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Medicine, Research & Experimental
Gentry King, Stacie Ittershagen, Luyang He, Ying Shen, Frank Li, Reginald Villacorta
Summary: This study described real-world treatment patterns and outcomes for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in the USA. The study found that most patients received first-line treatment in accordance with clinical practice guidelines, but overall survival remained poor. The study highlights the need for novel therapies to improve patient survival.
ADVANCES IN THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Ya-Chu Chang, Kevin Lin, Ryan M. Baxley, Wesley Durrett, Liangjun Wang, Olivera Stojkova, Maximilian Billmann, Henry Ward, Chad L. Myers, Anja-Katrin Bielinsky
Summary: DNA replication is regulated by post-translational modifications, including ubiquitination and SUMOylation, which are linked by the SUMO-targeted E3 ubiquitin ligases (STUbLs). RNF4, one of the mammalian STUbLs, is involved in DNA repair, but its role in replication was unclear. Through genetic screens, RNF4 mutants were found to depend on USP7 for survival in TP53-null cells. TKO cells displayed replication defects and increased cell death due to limited nuclear ubiquitin caused by proteasome inhibition.
Article
Biochemical Research Methods
Kevin Lin, Ya-Chu Chang, Ezequiel Marron Fernandez de Velasco, Kevin Wickman, Chad L. Myers, Anja-Katrin Bielinsky
Summary: This scalable approach for high-throughput compound screening utilizing a small custom library provides higher coverage and greater timepoint resolution compared to genome-wide screens.
Article
Multidisciplinary Sciences
Zhihua Kang, Pan Fu, Allen L. Alcivar, Haiqing Fu, Christophe Redon, Tzeh Keong Foo, Yamei Zuo, Caiyong Ye, Ryan Baxley, Advaitha Madireddy, Remi Buisson, Anja-Katrin Bielinsky, Lee Zou, Zhiyuan Shen, Mirit Aladjem, Bing Xia
Summary: BRCA2 is recruited to the replication fork through interaction with MCM10 to inhibit repriming and single-strand DNA gap formation after DNA damage. BRCA2-deficient cells exhibit radio-resistant DNA synthesis phenotype following DNA damage.
NATURE COMMUNICATIONS
(2021)