Review
Cell Biology
Stephanie Tye, George E. Ronson, Joanna R. Morris
Summary: The protection of stalled DNA replication forks requires the coordination of multiple recombination proteins and the utilization of nucleases in a different way than in homologous recombination. Despite similarities, the protection mechanism at stalled forks has unique features compared to the RAD51 loading step in homologous recombination.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2021)
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)
Editorial Material
Oncology
Barnabas Szakal, Dana Branzei
Summary: A new study has discovered the structure and function of the RAD51C-XRCC3 (CX3) heterodimer, which plays a critical role in replication fork stability and protection.
MOLECULAR ONCOLOGY
(2023)
Article
Multidisciplinary Sciences
Yashpal Rawal, Lijia Jia, Aviv Meir, Shuo Zhou, Hardeep Kaur, Eliza A. Ruben, Youngho Kwon, Kara A. Bernstein, Maria Jasin, Alexander B. Taylor, Sandeep Burma, Robert Hromas, Alexander V. Mazin, Weixing Zhao, Daohong Zhou, Elizabeth V. Wasmuth, Eric C. Greene, Patrick Sung, Shaun K. Olsen
Summary: This study reports cryogenic electron microscopy reconstructions of human BCDX2 in apo and ssDNA-bound states. The structures reveal the participation of the amino-terminal domains of RAD51B, RAD51C and RAD51D in inter-subunit interactions for complex formation and ssDNA-binding specificity. Single-molecule DNA curtain analysis provides insights into how BCDX2 enhances RAD51-ssDNA nucleoprotein filament assembly. Additionally, the cryogenic electron microscopy and functional analyses explain how RAD51C alterations found in patients with cancer inactivate DNA binding and the HR mediator activity of BCDX2.
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
Abdelghani Mazouzi, Sarah C. Moser, Federico Abascal, Bram van den Broek, Martin Del Castillo Velasco-Herrera, Ingrid van der Heijden, Maarten Hekkelman, Anne Paulien Drenth, Eline van der Burg, Lona J. Kroese, Kees Jalink, David J. Adams, Jos Jonkers, Thijn R. Brummelkamp
Summary: DNA interstrand crosslinks (ICLs) can hinder DNA replication and transcription if not repaired. The cellular response to ICLs requires coordination of various DNA repair mechanisms. FIRRM/C1orf112 was identified as a crucial factor in maintaining genome stability. It controls MUS81 chromatin loading to affect resolution of HR intermediates and plays a critical role in the response to ICLs encountered during DNA replication.
Review
Cell Biology
Christine M. Kondratick, M. Todd Washington, Maria Spies
Summary: DNA replication is complex and filled with obstacles that require decisions on whether to bypass, repair, restart damaged forks, or protect stalled forks. The involvement of multiple proteins in repair and restart mechanisms is crucial, but questions remain on how to ensure faithful genome duplication and prevent destabilization of the genome leading to cancer, cell death, and chemotherapeutic resistance. Various key players, including PCNA, DNA polymerases, molecular motors, and proteins involved in homologous recombination, play important roles in determining the mechanisms utilized to maintain genome integrity during DNA replication.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2021)
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
Anika Kuster, Nour L. Mozaffari, Oliver J. Wilkinson, Jessica L. Wojtaszek, Christina Zurfluh, Sara Przetocka, Dawid Zyla, Christine von Aesch, Mark S. Dillingham, R. Scott Williams, Alessandro A. Sartori
Summary: A peptide mimetic targeting CtIP was developed, which effectively inhibits CtIP activity, leading to impaired DNA repair and replication fork degradation, with selective toxicity to BRCA1-mutated cancer cells. This study provides a theoretical basis for the future development of CtIP-targeting compounds for cancer treatment.
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
Genetics & Heredity
Sharon B. Cantor
Summary: The debate over whether chemotherapy-induced DNA damage primarily results in DNA double strand breaks or single stranded DNA gaps has led to the realization that the latter may play a more significant role in cellular response and death. Proteins like BRCA1, BRCA2, and RAD51, known for their roles in DSB repair, also have critical functions in normal replication and the suppression and repair of replication gaps. Inducing widespread gaps proximal to treatment triggers apoptosis in a process independent of DSB induction.
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)
Article
Biochemistry & Molecular Biology
Ava Kwong, Cecilia Y. S. Ho, Vivian Y. Shin, Chun Hang Au, Tsun Leung Chan, Edmond S. K. Ma
Summary: This passage describes a 48-year-old female patient with biallelic pathogenic mutations of the BRCA1 gene, diagnosed with ovarian and breast cancer, and with a strong family history of breast and gynecological cancers.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Cell Biology
Isabel E. Wassing, Fumiko Esashi
Summary: RAD51, as the primary catalyst of homologous recombination (HR) in vertebrates, is not only involved in repairing double-stranded DNA breaks (DSBs), but its importance in DNA metabolism has also been increasingly recognized, with its function emerging as a double-edged sword in the interplay with DNA replication and the maintenance of genomic stability.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2021)
Article
Genetics & Heredity
Marc Tischkowitz, Judith Balmana, William D. Foulkes, Paul James, Joanne Ngeow, Rita Schmutzler, Nicoleta Voian, Myra J. Wick, Douglas R. Stewart, Tuya Pal
Summary: PALB2 germline pathogenic variants are associated with increased breast cancer risk and slightly smaller increased risk of pancreatic and possibly ovarian cancer. Management guidance for PALB2 heterozygotes is similar to that for BRCA1/2, with personalized risk estimates being crucial for decision-making. Further research is needed to address unanswered questions such as contralateral breast cancer risk and survival outcomes after cancer diagnosis.
GENETICS IN MEDICINE
(2021)
Article
Chemistry, Multidisciplinary
Miroslav Mrlik, Mario Spirek, Jassim Al-Khori, Ali Abdulrahman Ahmad, Jaroslav Mosnacek, Mariam Alali AlMaadeed, Peter Kasak
ARABIAN JOURNAL OF CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Barbora Stefanovie, Sarah R. Hengel, Jarmila Mlcouskova, Jana Prochazkova, Mario Spirek, Fedor Nikulenkov, Daniel Nemecek, Brandon G. Koch, Fletcher E. Bain, Liping Yu, Maria Spies, Lumir Krejci
NUCLEIC ACIDS RESEARCH
(2020)
Article
Cell Biology
Amaia Ercilla, Jan Benada, Sampath Amitash, Gijs Zonderland, Giorgio Baldi, Kumar Somyajit, Fena Ochs, Vincenzo Costanzo, Jiri Lukas, Luis Toledo
Article
Oncology
Stanislav Drapela, Prashant Khirsariya, Wytske M. van Weerden, Radek Fedr, Tereza Suchankova, Diana Buzova, Jan Cerveny, Ales Hampl, Martin Puhr, William R. Watson, Zoran Culig, Lumir Krejci, Kamil Paruch, Karel Soucek
MOLECULAR ONCOLOGY
(2020)
Article
Multidisciplinary Sciences
Marianna Feretzaki, Michaela Pospisilova, Rita Valador Fernandes, Thomas Lunardi, Lumir Krejci, Joachim Lingner
Article
Biochemistry & Molecular Biology
Chaoyou Xue, Lucia Molnarova, Justin B. Steinfeld, Weixing Zhao, Chujian Ma, Mario Spirek, Kyle Kaniecki, Youngho Kwon, Ondrej Belan, Katerina Krejci, Simon J. Boulton, Patrick Sung, Eric C. Greene, Lumir Krejci
Summary: RECQ5 is identified as an ATP-dependent single-stranded DNA motor protein that can translocate on various nucleoprotein complexes and dismantle RAD51-ssDNA filaments. Protein-protein interaction with RAD51 is crucial for RECQ5's functions, but its substrate specificity and ability to remove certain mutant RAD51 proteins suggest a complex regulatory role in genome maintenance.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Angelo Taglialatela, Giuseppe Leuzzi, Vincenzo Sannino, Raquel Cuella-Martin, Jen-Wei Huang, Foon Wu-Baer, Richard Baer, Vincenzo Costanzo, Alberto Ciccia
Summary: BRCA1/2 mutant tumor cells accumulate ssDNA gaps and spontaneous mutations during DNA replication due to repriming by PRIMPOL. This accumulation is exacerbated by depletion of RAD18 or inhibition of REV1-Pol zeta, with JH-RE-06 treatment resulting in reduced mutation rates and loss of viability in BRCA1/2-deficient cells. REV1-Pol zeta inhibitors show preferential toxicity toward HR-deficient cancer cells and may be a potential treatment strategy for BRCA1/2 mutant tumors.
Article
Multidisciplinary Sciences
Martin Kosar, Michele Giannattasio, Daniele Piccini, Apolinar Maya-Mendoza, Francisco Garcia-Benitez, Jirina Bartkova, Sonia I. Barroso, Helene Gaillard, Emanuele Martini, Umberto Restuccia, Miguel Angel Ramirez-Otero, Massimiliano Garre, Eleonora Verga, Miguel Andujar-Sanchez, Scott Maynard, Zdenek Hodny, Vincenzo Costanzo, Amit Kumar, Angela Bachi, Andres Aguilera, Jiri Bartek, Marco Foiani
Summary: The study reveals that Tpr depletion leads to transcription-dependent replication stress, DNA breaks, and genomic instability. It also shows an increased level of DNA-RNA hybrids in Tpr-deficient cells. Additionally, the research identifies a network of Tpr-interacting proteins involved in RNA processing and their depletion triggers cellular phenotypes similar to Tpr deficiency.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Mario Spirek, Martin R. G. Taylor, Ondrej Belan, Simon J. Boulton, Lumir Krejci
Summary: The RAD51 paralog complex RFS-1/RIP-1 controls the binding and dissociation of RAD-51 to ssDNA differently in the presence and absence of nucleotide cofactors. These nucleotide proofreading activities lead to a preferential accumulation of RAD-51-ssDNA complexes with optimal nucleotide content.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Anjali Mann, Miguel Angel Ramirez-Otero, Anna De Antoni, Yodhara Wijesekara Hanthi, Vincenzo Sannino, Giorgio Baldi, Lucia Falbo, Anna Schrempf, Sara Bernardo, Joanna Loizou, Vincenzo Costanzo
Summary: POLO plays an important role in repairing DNA double-strand breaks in HR-defective tumors. It is found that POLO processes stalled Okazaki fragments, preventing the accumulation of ssDNA gaps on lagging strands in the absence of RAD51. Inhibition of POLO's DNA polymerase activity leads to unprotected fork gaps, which are cleaved by the MRE11-NBS1-CtIP endonuclease, causing asymmetric single-ended DSBs that impede the survival of BRCA2-defective cells.
Article
Cell Biology
Chandler E. Moore, Selin E. Yalcindag, Hanna Czeladko, Ramya Ravindranathan, Yodhara Wijesekara Hanthi, Juliana C. Levy, Vincenzo Sannino, Detlev Schindler, Alberto Ciccia, Vincenzo Costanzo, Andrew E. H. Elia
Summary: In this study, a new role for the Fanconi Anemia-associated gene RFWD3 is uncovered. It is shown that RFWD3 promotes the recruitment of DNA translocase ZRANB3 to stalled replication forks and DNA damage sites, thereby stimulating fork remodeling. This is achieved through RFWD3-mediated PCNA ubiquitination and interaction with ZRANB3, providing a mechanism for RFWD3-dependent recruitment of ZRANB3.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Lucia Falbo, Vincenzo Costanzo
Summary: Research has shown that in early embryonic development of certain metazoans, there is a transition in the number of replication origins to ensure accurate DNA replication. This novel form of epigenetic memory may impact various areas of vertebrate biology.
Article
Multidisciplinary Sciences
James Alexander Booth, Mario Spirek, Tekle Airgecho Lobie, Kirsten Skarstad, Lumir Krejci, Magnar Bjoras
SCIENTIFIC REPORTS
(2020)