Review
Genetics & Heredity
Rachel Adihe Lokanga, Daman Kumari, Karen Usdin
Summary: The human genome contains fragile chromosomal regions that demonstrate breaks, gaps, or constrictions under replication stress. Common fragile sites are induced by aphidicolin, while rare fragile sites are induced by folate stress. Different fragile sites have distinct molecular bases and can cause chromosomal abnormalities, some of which are associated with intellectual disabilities.
FRONTIERS IN GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Yongze Yu, Weiwei Xu, Canxin Wen, Simin Zhao, Guangyu Li, Ran Liu, Zi-Jiang Chen, Yingying Qin, Jinlong Ma, Yajuan Yang, Shidou Zhao
Summary: In this study, Ube2t knockout mice showed defects in the proliferation of primordial germ cells (PGCs), resulting in severe loss of germ cells after birth. Deletion of UBE2T exacerbated DNA damage and activated the p53 pathway. The study also revealed that UBE2T resolves transcription-replication conflicts, protects common fragile sites, and promotes mitotic DNA synthesis to maintain the genomic stability of PGCs. Overall, these findings provide new insights into the function and regulatory mechanisms of the Fanconi anemia pathway in ensuring the normal development of PGCs.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Review
Biology
Benjamin S. Simpson, Hayley Pye, Hayley C. Whitaker
Summary: Recent developments in sequencing the cancer genome have identified 16 signatures of structural variants across 38 tumour types, with some of the variants occurring at fragile sites like NAALADL2. These copy-number variations at fragile sites may have a significant impact on cell signalling.
COMMUNICATIONS BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Sumedha Agashe, Chinnu Rose Joseph, Teresa Anne Clarisse Reyes, Demis Menolfi, Michele Giannattasio, Anja Waizenegger, Barnabas Szakal, Dana Branzei
Summary: The study reveals that Smc5/6 acts together with Top3 within the STR complex to regulate the DNA processing activities of Sgs1 and Top3, maintaining genome structural integrity and mediating DNA replication completion.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Laura J. Bailey, Rebecca Teague, Peter Kolesar, Lewis J. Bainbridge, Howard D. Lindsay, Aidan J. Doherty
Summary: Replication stress and DNA damage can stall replication forks and impede genome synthesis. PrimPol, regulated by PLK1 phosphorylation, plays a crucial role in damage tolerance pathway during S phase to ensure efficient genome duplication and prevent genomic instability.
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.
Review
Genetics & Heredity
Fang Ji, Xinli Zhu, Hongwei Liao, Liujian Ouyang, Yingfei Huang, Madiha Zahra Syeda, Songmin Ying
Summary: This review provides an update on the research progress of common fragile sites (CFSs), including mapping and sequencing techniques, as well as hypotheses on the fragility origin of CFSs. By analyzing the locations, sequences, and replication/transcription of CFSs, this review presents the latest research status of CFSs and potentially offers a new framework for future CFS research.
FRONTIERS IN GENETICS
(2022)
Article
Multidisciplinary Sciences
Michael Kronenberg, Michael F. Carey
Summary: Head-on (HO) collisions between the DNA replication machinery and RNA polymerase over R-loop forming sequences (RLFS) are genotoxic, leading to replication fork blockage and DNA breaks. This study explores the relationship between transcription and replication and suggests that HO collisions are avoided through transcriptional regulatory mechanisms.
Article
Cell Biology
Maria Moreno-del Alamo, Begona Carrasco, Ruben Torres, Juan Carlos Alonso
Summary: The study reveals that Bacillus subtilis PcrA interacts with RNA polymerase to mitigate replication-transcription conflicts. Depletion of PcrA can be partially suppressed by rnhB inactivation, but significantly reduces cell viability when rnhC or dinG are inactivated. PcrA, in collaboration with RnhC or DinG, plays a role in removing R-loops to preserve genomic integrity.
Article
Biochemistry & Molecular Biology
Sabrina Wegmann, Cindy Meister, Christian Renz, George Yakoub, Hans-Peter Wollscheid, Diane T. Takahashi, Ivan Mikicic, Petra Beli, Helle D. Ulrich
Summary: This study presents a strategy for reprogramming the linkage of polyubiquitin chains using tailor-made ubiquitin ligases, and demonstrates that altering the features of a polyubiquitin chain can change the fate of the modified substrate, using the budding yeast replication factor PCNA as a model case. The study also provides evidence for redundancy between structurally similar linkages and shows that the method can be generalized to targets beyond PCNA.
Review
Biochemistry & Molecular Biology
John R. Walker, Xu-Dong Zhu
Summary: This article discusses the important role of CSB in resolving replication stress and maintaining genetic integrity through different pathways, and also explores the implications of CSB in cancer therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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
Biochemistry & Molecular Biology
Nicole L. Batenburg, Shixin Cui, John R. Walker, Herb E. Schellhorn, Xu-Dong Zhu
Summary: CSB protein relies on its WHD domain to regulate RNAPII abundance at PPP sites of actively transcribed genes, independent of its ubiquitin-binding activity. Mutations that affect its ability to promote RNAPII occupancy at PPP sites suggest a separation between CSB-mediated RNAPII occupancy and repair of cisplatin-induced DNA damage.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Chiaki Noguchi, Lucy Wang, Mihir Shetty, Joshua Chang Mell, Christian Sell, Eishi Noguchi
Summary: The key to longevity assurance lies in the nutrient-sensing mTOR pathway. Maf1 has been identified as a critical downstream regulator of the mTOR pathway, playing a crucial role in extending lifespan through its control of RNA polymerase III-directed transcription. This study highlights the importance of Maf1 in promoting genomic integrity and maintaining normal lifespan under conditions of DNA replication-transcription conflicts.
Review
Biochemistry & Molecular Biology
Ines Paniagua, Jacqueline J. L. Jacobs
Summary: TLS polymerases, originally known for their error-prone functions in bypassing DNA lesions, have been found to play pivotal roles in various cellular processes. Besides lesion bypass, these enzymes are involved in DNA replication, DNA repair, epigenetics, immune signaling, and viral infection. Due to their multitasking ability to alleviate replication stress, TLS polymerases are both a cellular dependency and a critical vulnerability of cancer cells. This review highlights the current and emerging strategies for targeting TLS polymerases in cancer therapy.
Article
Genetics & Heredity
Mengling Qi, Peter D. Stenson, Edward Ball, John A. Tainer, Albino Bacolla, Hildegard Kehrer-Sawatzki, David N. Cooper, Huiying Zhao
Summary: Microdeletions and gross deletions are important causes of human inherited disease, and their genomic locations are influenced by the DNA sequence environment. This study analyzed the DNA sequences near breakpoint junctions and found correlations between the frequencies of non-B DNA-forming repeats, GC-content, specific sequence motifs, and deletion length. The study also proposed using a deletion length cut-off of 25-30 bp to functionally distinguish microdeletions from gross deletions.
Article
Biochemistry & Molecular Biology
Farid Boulad, Aurelio Maggio, Xiuyan Wang, Paolo Moi, Santina Acuto, Friederike Kogel, Chayamon Takpradit, Susan Prockop, Jorge Mansilla-Soto, Annalisa Cabriolu, Ashlesha Odak, Jinrong Qu, Keyur Thummar, Fang Du, Lingbo Shen, Simona Raso, Rita Barone, Rosario Di Maggio, Lorella Pitrolo, Antonino Giambona, Maura Mingoia, John K. Everett, Pascha Hokama, Aoife M. Roche, Vito Adrian Cantu, Hriju Adhikari, Shantan Reddy, Eric Bouhassira, Narla Mohandas, Frederic D. Bushman, Isabelle Riviere, Michel Sadelain
Summary: This study reports the 6-8-year follow-up of four adult patients with transfusion-dependent beta-thalassemia who received autologous CD34(+) cells transduced with a lentiviral globin vector. The findings suggest that non-myeloablative conditioning can achieve durable stem cell engraftment, but a minimum CD34(+) cell transduction requirement is necessary for effective therapy. The study highlights the importance of monitoring patients with globin vectors.
Article
Hematology
Silvia Alvarez, Ana C. da Silva Almeida, Robert Albero, Mayukh Biswas, Angelica Barreto-Galvez, Thomas S. Gunning, Anam Shaikh, Tomas Aparicio, Agnieszka Wendorff, Erich Piovan, Pieter Van Vlierberghe, Steven Gygi, Jean Gautier, Advaitha Madireddy, Adolfo A. Ferrando
Summary: Research has shown that the PHF6 gene is involved in multiple molecular mechanisms, including nucleosome remodeling and DNA repair. After DNA damage, PHF6 localizes to the sites of injury and its absence impairs the resolution of DNA breaks. Furthermore, PHF6 specifically associates with difficult-to-replicate heterochromatin, making it an important regulator of genomic stability.
Article
Biochemistry & Molecular Biology
Sakshi Jasra, Orsi Giricz, Rachel Zeig-Owens, Kith Pradhan, David G. Goldfarb, Angelica Barreto-Galvez, Alexander J. Silver, Jiahao Chen, Srabani Sahu, Shanisha Gordon-Mitchell, Gaurav S. Choudhary, Srinivas Aluri, Tushar D. Bhagat, Aditi Shastri, Cosmin A. Bejan, Shannon S. Stockton, Travis P. Spaulding, Victor Thiruthuvanathan, Hiroki Goto, Jeannine Gerhardt, Syed Hissam Haider, Arul Veerappan, Matthias Bartenstein, George Nwankwo, Ola Landgren, Michael D. Weiden, Jacqueline Lekostaj, Ryan Bender, Frederick Fletcher, Lee Greenberger, Benjamin L. Ebert, Ulrich Steidl, Britta Will, Anna Nolan, Advaitha Madireddy, Michael R. Savona, David J. Prezant, Amit Verma
Summary: The terrorist attacks on the World Trade Center led to a high burden of somatic mutations in blood cells among first responders, raising their risk for cancer. Exposure to WTC particulate matter caused dysregulation of DNA replication and increased mutation burden in mice. Enhanced screening and preventative efforts are needed for first responders to the WTC disaster.
Article
Oncology
Xiangliang Yuan, Yimin Duan, Yi Xiao, Kai Sun, Yutao Qi, Yuan Zhang, Zamal Ahmed, Davide Moiani, Jun Yao, Hongzhong Li, Lin Zhang, Arseniy E. Yuzhalin, Ping Li, Chenyu Zhang, Akosua Badu-Nkansah, Yohei Saito, Xianghua Liu, Wen-Ling Kuo, Haoqiang Ying, Shao-Cong Sun, Jenny C. Chang, John A. Tainer, Dihua Yu
Summary: The study found that vitamin E has a significant impact on the survival rate of patients treated with immune checkpoint therapy, enhancing the efficacy of ICT and promoting antigen presentation by inhibiting SHP1 to activate anti-tumor T-cell immunity.
Article
Cell Biology
Alexandra Berroyer, Albino Bacolla, John A. Tainer, Nayun Kim
Summary: Top1 plays a critical role in maintaining stability at G4-forming genomic loci, and its inhibition by anticancer drugs can lead to increased genomic instability. CPT-resistant Top1 mutants enhance G4-induced recombination and synergize with Nsr1 to exacerbate genomic instability, complicating patient treatment.
Article
Biotechnology & Applied Microbiology
Gabriel Quintanilha-Peixoto, Marina Pupke Marone, Fabio Trigo Raya, Juliana Jose, Adriele Oliveira, Paula Luize Camargos Fonseca, Luiz Marcelo Ribeiro Tome, Dener Eduardo Bortolini, Rodrigo Bentes Kato, Daniel S. Araujo, Ruth B. De-Paula, Yesid Cuesta-Astroz, Elizabeth A. A. Duarte, Fernanda Badotti, Vasco Ariston de Carvalho Azevedo, Bertram Brenig, Ana Cristina Fermino Soares, Marcelo Falsarella Carazzolle, Goncalo Amarante Guimaraes Pereira, Eric Roberto Guimaraes Rocha Aguiar, Aristoteles Goes-Neto
Summary: Aspergillus welwitschiae is a pathogenic fungus causing bole rot disease in sisal, affecting the fiber production in Brazil. Comparative genomics analysis reveals the conflicting molecular identity of this species and identifies genes potentially associated with the pathogenicity in sisal.
Article
Biochemistry & Molecular Biology
Madhura Deshpande, Theodore Paniza, Nahed Jalloul, Gouri Nanjangud, Jerzy Twarowski, Amnon Koren, Nikica Zaninovic, Qiansheng Zhan, Kalyani Chadalavada, Anna Malkova, Hossein Khiabanian, Advaitha Madireddy, Zev Rosenwaks, Jeannine Gerhardt
Summary: Germline mutations in the BRCA genes are associated with a higher risk of carcinogenesis, and the mechanisms triggering mutagenesis are still unclear. This study found that the BRCA genes are fragile sites with replication forks stalling and DNA breaks. In addition, under stress, error-prone repair of stalled forks leads to mutations, including complex genomic rearrangements at the BRCA genes.
Article
Multidisciplinary Sciences
Michael B. Heskett, Athanasios E. Vouzas, Leslie G. Smith, Phillip A. Yates, Christopher Boniface, Eric E. Bouhassira, Paul Spellman, David M. Gilbert, Mathew J. Thayer
Summary: Heskett et al. describe a class of long non-coding RNA genes called ASARs, which are essential for the replication and stability of human chromosomes and show distinct epigenetic regulation between subclonal lineages. They identified hundreds of autosomal loci with epigenetically controlled, allele-restricted behavior in expression and replication timing of coding and noncoding genes, different from genomic imprinting. Disruption of ASAR genes results in chromosome-wide delayed replication and instability.
NATURE COMMUNICATIONS
(2022)
Article
Genetics & Heredity
Cong Fan, Ken Chen, Yukai Wang, Edward Ball, Peter D. Stenson, Matthew Mort, Albino Bacolla, Hildegard Kehrer-Sawatzki, John A. Tainer, David N. Cooper, Huiying Zhao
Summary: This study systematically analyzed key topological features at the DNA, RNA, and protein levels in order to construct a tool for distinguishing pathogenic repeat expansions. Pathogenic repeat expansions were found to exhibit specific features at the DNA, RNA, and protein levels and exert a synergistic influence on the gene expression pathway.
Article
Biochemistry & Molecular Biology
Amer Bralic, Muhammad Tehseen, Mohamed A. Sobhy, Chi-Lin Tsai, Lubna Alhudhali, Gang Yi, Jina Yu, Chunli Yan, Ivaylo Ivanov, Susan E. Tsutakawa, John A. Tainer, Samir M. Hamdan
Summary: Nucleotide excision repair (NER) is crucial for removing bulky DNA lesions, and this study reveals that the XPG nuclease plays a dual role in lesion recognition and excision. XPG stimulates TFIIH-dependent dsDNA unwinding and cleavage activity, and this coordination requires a DNA bubble longer than 15 nucleotides.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Aleem Syed, Frantisek Filandr, Jeffrey Patterson-Fortin, Albino Bacolla, Ramya Ravindranathan, Jia Zhou, Drew T. Mcdonald, Mohammed E. Albuhluli, Amy Verway-Cohen, Joseph A. Newman, Miaw-Sheue Tsai, Darin E. Jones, David C. Schriemer, Alan D. D'Andrea, John A. Tainer
Summary: Polymerase theta (Pol θ) is involved in DNA replication and repair, and its inhibition is deadly for BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB), an ATPase inhibitor of Pol θ, is being tested as an anti-cancer drug in clinical trials. This study reveals the molecular mechanism of NVB-mediated Pol θ inhibition, showing that NVB blocks DNA binding by binding to an allosteric site.
NUCLEIC ACIDS RESEARCH
(2023)
Correction
Biochemistry & Molecular Biology
A. Bacolla
NUCLEIC ACIDS RESEARCH
(2022)
Review
Biochemistry & Molecular Biology
Atanu Mondal, Apoorva Bhattacharya, Vipin Singh, Shruti Pandita, Albino Bacolla, Raj K. Pandita, John A. Tainer, Kenneth S. Ramos, Tej K. Pandita, Chandrima Das
Summary: From initiation to progression, cancer cells experience a variety of internal and external stresses, leading to changes in their epigenome and transcriptome. Understanding the stress response pathways of cancer cells is crucial for developing novel anticancer therapies.
MOLECULAR AND CELLULAR BIOLOGY
(2022)