Article
Multidisciplinary Sciences
Izumi Kaneko, Tsubasa Nishi, Shiroh Iwanaga, Masao Yuda
Summary: Plasmodium parasites, the causative agents of malaria, undergo complex cell-type changes during their lifecycle, but the mechanisms of gene regulation involved in these changes are still unknown. In this study, researchers discovered that gSNF2, a chromatin remodeling ATPase, is essential for the differentiation of male gametocytes. Disruption of gSNF2 resulted in the inability of male gametocytes to develop into gametes. Further analysis revealed that gSNF2 is recruited to male-specific genes through a specific cis-acting element and its disruption led to decreased expression of over a hundred target genes. These findings suggest that chromatin remodeling plays a crucial role in cell-type changes in the Plasmodium lifecycle.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Ilana M. Nodelman, Zhongtian Shen, Robert F. Levendosky, Gregory D. Bowman
Summary: This study reveals that the autoinhibitory elements of the yeast Chd1 remodeler block nucleosome sliding by preventing the initiation of twist defects, controlling the positioning of nucleosomes. The chromodomains and bridge of the remodeler reinforce each other to block sliding when the DNA-binding domain is not bound to DNA, targeting nucleotide-free and ADP-bound states of the ATPase motor. This uncouples the ATP binding/hydrolysis cycle from DNA translocation around the histone core, suggesting a mechanism for regulating chromatin remodeling.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Jonathan Markert, Karolin Luger
Summary: This article discusses the organization of genomic DNA in eukaryotes as arrays of nucleosomes, highlighting the role of ATP-dependent remodelers in modulating nucleosome structure. These remodelers utilize specific nucleosome features to bind and alter nucleosomes, overcoming the barrier posed by the tight interaction between DNA and histones.
TRENDS IN BIOCHEMICAL SCIENCES
(2021)
Article
Biology
Leonhard A. Karl, Lorenzo Galanti, Susanne C. S. Bantele, Felix Metzner, Barbara Safaric, Lional Rajappa, Benjamin Foster, Vanessa Borges Pires, Priyanka Bansal, Erika Chacin, Jerome Basquin, Karl E. Duderstadt, Christoph F. Kurat, Till Bartke, Karl-Peter Hopfner, Boris Pfander
Summary: Fun30 is a prototype of nucleosome remodelers involved in DNA repair and gene silencing. It acts as a single-subunit nucleosome remodeler, but its molecular mechanisms are poorly understood. Through structural analysis, a conserved domain termed SAM-key is identified, and its deletion leads to defects in DNA repair and gene silencing. The SAM-key helix interacts with a critical subdomain to regulate ATPase activity, highlighting the importance of allosteric activation for Fun30 enzymes.
LIFE SCIENCE ALLIANCE
(2023)
Article
Biology
Changkun Hu, Taylor Bugbee, Rachel Palinski, Ibukun A. Akinyemi, Michael T. McIntosh, Thomas MacCarthy, Sumita Bhaduri-McIntosh, Nicholas Wallace, Wolf-Dietrich Heyer
Summary: The E6 protein of beta-human papillomavirus (HPV8) delays DNA double strand break (DSB) repair and promotes an alternative DSB repair pathway known as alternative end joining (Alt-EJ). HPV8 E6 also inhibits the normal DSB repair mechanism by binding to p300. This study fills the knowledge gap of how DSB is repaired in cells with HPV8 E6 and highlights the mutagenic consequences of HPV8 E6 mediated p300 destabilization. It supports the hypothesis that beta-HPV promotes cancer formation by increasing genomic instability.
Article
Multidisciplinary Sciences
Zhuoyi Liang, Vipul Kumar, Marie Le Bouteiller, Jeffrey Zurita, Josefin Kenrick, Sherry G. Lin, Jiangman Lou, Jianqiao Hu, Adam Yongxin Ye, Cristian Boboila, Frederick W. Alt, Richard L. Frock
Summary: The study demonstrates that in Lig4-deficient G1-arrested progenitor B cells, Ku-dependent blockage of A-EJ leads to functional endjoining suppression. However, joining of RAG-generated DSBs in Ku70-deficient or Ku70/Lig4 double-deficient cells occurs through a translocation-like A-EJ mechanism.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Hubert Fleury, Myles K. MacEachern, Clara M. Stiefel, Roopesh Anand, Colin Sempeck, Benjamin Nebenfuehr, Kelper Maurer-Alcala, Kerri Ball, Bruce Proctor, Ondrej Belan, Erin Taylor, Raquel Ortega, Benjamin Dodd, Laila Weatherly, Djelika Dansoko, Justin W. Leung, Simon J. Boulton, Nausica Arnoult
Summary: In this study, the APE2 nuclease was identified as an effector of MMEJ repair pathway. It was found that APE2's function in MMEJ depends on its nuclease activity and a previously uncharacterized domain is required for its recruitment to DSBs. This previously unappreciated role of APE2 in MMEJ contributes to the addiction of HRD cells to APE2, which could be exploited in the treatment of cancer.
Article
Biochemistry & Molecular Biology
Suleman S. Hussain, Rahul Majumdar, Grace M. Moore, Himanshi Narang, Erika S. Buechelmaier, Maximilian J. Bazil, Pavithran T. Ravindran, Jonathan E. Leeman, Yi Li, Manisha Jalan, Kyrie S. Anderson, Andrea Farina, Rekha Soni, Neeman Mohibullah, Edin Hamzic, Xiaoqing Rong-Mullins, Christopher Sifuentes, Rama R. Damerla, Agnes Viale, Simon N. Powell, Daniel S. Higginson
Summary: This study developed a Cas9-based repair system with simplified repair outcomes and converted it into ddPCR readouts for easier use in more laboratories. The experiment found that the key Alt-EJ factor Pol theta only accounts for 50% of total Alt-EJ, SSTR requires BRCA1 and MRE11 activity, and BRCA1 promotes Alt-EJ usage at two-ended DSBs.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Thomas L. Genetta, Joshua C. Hurwitz, Evan A. Clark, Benjamin T. Herold, Shadi Khalil, Tarek Abbas, James M. Larner
Summary: The transcriptional repressor ZEB1 interacts with 53BP1 and enhances Non-Homologous End Joining (NHEJ) repair while inhibiting Homologous Recombination (HR) repair. It also promotes resection at DSBs and confers PARP inhibitor (PARPi) sensitivity on BRCA1-deficient cells. These findings suggest that ZEB1 levels may serve as a predictive biomarker for PARPi response in BRCA1-deficient tumors.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Naihua N. Gong, Leela Chakravarti Dilley, Charlette E. Williams, Emilia H. Moscato, Milan Szuperak, Qin Wang, Matthew Jensen, Santhosh Girirajan, Tiong Yang Tan, Matthew A. Deardorff, Dong Li, Yuanquan Song, Matthew S. Kayser
Summary: The chromatin remodeler ISWI is essential for adult fly sleep and its loss leads to disrupted circadian rhythms, memory, and social behavior. Expressing human ISWI homologs in flies can rescue adult phenotypes to different extents, highlighting the importance of chromatin remodeling machinery for sleep circuit formation in neurodevelopmental disorders.
Review
Biochemistry & Molecular Biology
Wanyu Bai, Bo Zhao, Mingyu Gu, Junchao Dong
Summary: This review discusses the mechanisms of alternative end-joining (A-EJ) in antigen receptor gene recombination and class switch recombination (CSR), and its implications for lymphoid development and chromosomal translocations.
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
(2022)
Article
Biology
Simon Magin, Prabodha Kumar Meher, George Iliakis
Summary: Alt-EJ is a DNA repair pathway that can be utilized by vertebrate cells to repair DNA double-strand breaks, but its engagement is linked to genomic instability. Exposure to ionizing radiation and treatment with nucleoside analogs can sensitize cells to radiation by increasing alt-EJ engagement and suppressing homologous recombination. This pathway shift may reflect a compensatory response to HR suppression in S and G2 phase cells.
RADIATION RESEARCH
(2021)
Article
Cell Biology
Xikui Sun, Jingning Bai, Jiejie Xu, Xiaoli Xi, Mingyu Gu, Chengming Zhu, Hongman Xue, Chun Chen, Junchao Dong
Summary: The study demonstrates the critical roles of CtIP and Mre11 in mediating A-EJ CSR, while DNA2 and BLM are involved in long S region DSB resection. Additionally, ATM and its kinase activity can function partly independently of CtIP/Mre11 to mediate A-EJ switching.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Colette B. Rogers, Rachel E. Kram, Kevin Lin, Chad L. Myers, Alexandra Sobeck, Eric A. Hendrickson, Anja-Katrin Bielinsky
Summary: Activation of the Fanconi anemia (FA) pathway is crucial for preventing chromosome translocations referred to as "radials" after treatment with mitomycin C (MMC). Radials induced by MMC are dependent on DNA polymerase theta (POLq)-mediated alternative end joining (A-EJ) in FA-deficient cells, specifically involving POL theta and DNA ligase III. Blocking POLq in FA-deficient cells eliminates radials and leads to the accumulation of breaks at common fragile sites. These findings provide mechanistic insights into the formation of radials and offer potential therapeutic strategies for FA pathway-deficient cancers using POLq inhibitors.
Review
Cell Biology
Antonella Lettieri, Roberto Oleari, Alyssa J. J. Paganoni, Cristina Gervasini, Valentina Massa, Alessandro Fantin, Anna Cariboni
Summary: CHD7 is a chromatin remodeler protein that controls gene expression by forming multi-protein complexes with specific transcription factors. It plays roles in both the central nervous system and the peripheral nervous system, as well as organs colonized by neural crest cells such as the heart. Mutated CHD7 is associated with CHARGE syndrome and various neoplastic transformations. Recent evidence suggests genetic interactions between CHD7 and semaphorins in developmental processes and cancer progression.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Blandine Roux, Camille Vaganay, Jesse D. Vargas, Gabriela Alexe, Chaima Benaksas, Bryann Pardieu, Nina Fenouille, Jana M. Ellegast, Edyta Malolepsza, Frank Ling, Gaetano Soda Rol, Linda Ross, Yana Pikman, Amy S. Y. Conwa, Yangzhong Tang, Tony Wu, Daniel J. Anderson, Ronan Le Moigne, Ha N-Jie Zhou, Frederic Luciano, Christina R. Hartigan, Ilene Galinsky, Daniel J. DeAngelo, Richard M. Stone, Patrick Auberger, Monica Schenone, Steven A. Ca Rr, Josee Guirouilh-Barbat, Bernard Lopez, Mehdi Khaled, Kasper Lage, Olivier Hermine, Michael T. Hemann, Alexandre Puissant, Kimberly Stegmaier, Lina Benajiba
Summary: Research has identified VCP as a critical vulnerability in AML, with chemical inhibition of VCP having a strong impact. Through mass spectrometry-based analysis of the VCP interactome and phospho-signaling studies, it was found that VCP is crucial for ATM kinase activation and subsequent homologous recombination DNA repair in AML.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Review
Genetics & Heredity
Simon Willaume, Emilie Rass, Paula Fontanilla-Ramirez, Angela Moussa, Paul Wanschoor, Pascale Bertrand
Summary: The article discusses the mechanisms involved in DSB repair, replicative stress management, and their consequences, as well as the emerging links between key components of the nuclear envelope, lamins, DNA repair, replicative stress management, and inflammation.
Review
Oncology
Gabriel Matos-Rodrigues, Emmanuelle Martini, Bernard S. Lopez
Summary: Homologous recombination (HR) is a crucial DNA repair pathway for genome stability, and mutations in many HR genes are associated with cancer risk. Transgenic mouse models are important for studying HR in tumorigenesis, but invalidating HR genes can lead to embryonic lethality in mammals. Complex strategies have been developed to overcome this challenge and investigate the impact of HR defects on tumorigenesis in vivo. The central HR factor, RAD51, has not been fully characterized in vivo and its inactivation is not linked to cancer predisposition, highlighting the RAD51 paradox. Mouse models can be valuable for developing targeted cancer therapies and understanding the mechanisms of HR inactivation-driven tumorigenesis in vivo.
Article
Biochemistry & Molecular Biology
Gaelle Pennarun, Julien Picotto, Laure Etourneaud, Anna-Rita Redavid, Anais Certain, Laurent R. Gauthier, Paula Fontanilla-Ramirez, Didier Busso, Caroline Chabance-Okumura, Benoit Theze, Francois D. Boussin, Pascale Bertrand
Summary: The study reveals that overexpression of lamin B1 disrupts the shelterin complex, leading to telomere instability, telomeric fusions, and telomere losses in human cells. Additionally, new interactions between lamin B1 and shelterin proteins may play a crucial role in telomere stability.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Chemistry, Physical
Sandrine Ragu, Olivier Pietrement, Bernard S. Lopez
Summary: DNA manipulation is crucial for many biotechnological prospects and medical applications, and the natural magnesium silicate clay mineral sepiolite, with its capacity to bind to DNA, shows potential as a useful tool in these fields. Sepiolite is also advantageous due to its low cost, non-toxic nature, and non-carcinogenic properties.
CLAYS AND CLAY MINERALS
(2021)
Article
Biochemistry & Molecular Biology
Amelie Schellenbauer, Marie-Noelle Guilly, Romain Grall, Romain Le Bars, Vincent Paget, Thierry Kortulewski, Haser Sutcu, Cecile Mathe, Marie Hullo, Denis Biard, Francois Leteurtre, Vilma Barroca, Youenn Corre, Lamya Irbah, Emilie Rass, Benoit Theze, Pascale Bertrand, Jeroen A. A. Demmers, Josee Guirouilh-Barbat, Bernard S. Lopez, Sylvie Chevillard, Jozo Delic
Summary: cNHEJ is a key DNA repair pathway in mammalian cells, regulated by phosphorylation of Ku70 at DNA damage sites, leading to recruitment of RNA Pol II and formation of phospho-53BP1 foci. Phosphorylation is also necessary for the release of Ku70 from the repair complex, and non-phosphorylatable forms may cause chromosomal instability. Cells expressing pKu70 are protected against joining of distal DNA ends, highlighting the essential role of pKu70 in maintaining genome stability.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Ayeong So, Elodie Dardillac, Ali Muhammad, Catherine Chailleux, Laura Sesma-Sanz, Sandrine Ragu, Eric Le Cam, Yvan Canitrot, Jean Yves Masson, Pauline Dupaigne, Bernard S. Lopez, Josee Guirouilh-Barbat
Summary: Selection of DSB repair pathway is crucial for genetic stability. RAD51 plays a role in preventing nonconservative repair by controlling the second step of the repair process in human cells. RAD51's DNA binding ability is required for inhibiting SSA/A-EJ, not GC.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Julien Ouvrard, Lisa Muniz, Estelle Nicolas, Didier Trouche
Summary: siRNAs can induce transcriptional silencing of chromatin-associated noncoding RNA through base-pairing with the target sequence. Transcriptional silencing occurs only in cis, and both Ago1 and Ago2 are involved.
MOLECULAR AND CELLULAR BIOLOGY
(2022)
Review
Genetics & Heredity
Emilie Rass, Simon Willaume, Pascale Bertrand
Summary: Double-strand breaks (DSBs) are toxic lesions and the protein 53BP1 plays a crucial role in choosing the repair mechanism for DSBs. By preventing DSB end resection, 53BP1 promotes non-homologous end joining (NHEJ) and maintains genome stability. This review focuses on the mechanism of 53BP1 recruitment to damage and recent studies describing novel mechanisms for keeping 53BP1 at a distance from DSBs.
Article
Chemistry, Multidisciplinary
David Adame Brooks, Olivier Pietrement, Elodie Dardillac, Ayesha Jayantha, Manuel A. Lores Guevara, Fidel Antonio Castro-Smirnov, Pilar Aranda, Eduardo Ruiz-Hitzky, Bernard S. Lopez
Summary: Research shows that sonication can improve the dispersion performance of sepiolite, a naturally occurring clay silicate, and enhance its interaction with biomacromolecules such as bovine serum albumin. Sonication also reduces the toxicity of sepiolite in mammalian cells.
Article
Biochemistry & Molecular Biology
Sandrine Ragu, Nathalie Droin, Gabriel Matos-Rodrigues, Aurelia Barascu, Sylvain Caillat, Gabriella Zarkovic, Capucine Siberchicot, Elodie Dardillac, Camille Gelot, Josee Guirouilh-Barbat, J. Pablo Radicella, Alexander A. Ishchenko, Jean-Luc Ravanat, Eric Solary, Bernard S. Lopez
Summary: In human primary cells, a noncanonical cellular response specific to nonblocking replication stress is discovered. This response generates reactive oxygen species (ROS) and activates detoxification genes. ROS are produced by DUOX1/DUOX2 and controlled by NF-kappa B.
CELL DEATH AND DIFFERENTIATION
(2023)
Review
Genetics & Heredity
Gaelle Pennarun, Julien Picotto, Pascale Bertrand
Summary: The nuclear envelope plays essential roles in protecting the genome and also in various important functions, including chromatin organization and DNA replication and repair. Changes in the nuclear envelope are associated with multiple human diseases and cancer cells. Telomeres, which are crucial for genome stability, interact with the nuclear envelope in yeast, where their tethering to the envelope is critical for their maintenance. Recent studies have revealed close ties between mammalian telomeres and the nuclear envelope, highlighting their important roles in maintaining genome integrity.
Review
Cell Biology
Melissa Thomas, Caroline Dubacq, Elise Rabut, Bernard S. Lopez, Josee Guirouilh-Barbat
Summary: Homologous recombination (HR) is an evolutionarily conserved pathway that plays a crucial role in genome plasticity. RAD51, through its canonical catalytic strand invasion/exchange activity, is a key player in HR. However, the invalidation of RAD51 is not classified as cancer-prone, indicating other noncanonical roles of RAD51. These roles include preventing mutagenic DNA repair, involvement in replication fork management, participation in RNA-mediated processes, and contribution to brain development.
Article
Cell Biology
Melissa Leriche, Clara Bonnet, Jagannath Jana, Gita Chhetri, Sabrina Mennour, Sylvain Martineau, Vincent Pennaneach, Didier Busso, Xavier Veaute, Pascale Bertrand, Sarah Lambert, Kumar Somyajit, Patricia Uguen, Stephan Vagner
Summary: RNA-binding protein 53BP1 is found to directly interact with Okazaki fragments and its recruitment is affected by RNA enzyme processing. RNA primers contribute to the recruitment of 53BP1 at replication forks, and depletion of 53BP1 leads to the accumulation of S-phase poly(ADP-ribose).
Article
Biochemistry & Molecular Biology
Gabriel Matos-Rodrigues, Josee Guirouilh-Barbat, Emmanuelle Martini, Bernard S. Lopez
Summary: Genetic instability in cancer cells is often linked to homologous recombination (HR) deficiency, which can lead to cancer predisposition. While RAD51 plays a vital role in HR, overexpression of RAD51 is associated with poor prognosis in various tumors. The differences between RAD51 and other HR partners in terms of cancer susceptibility form what is referred to as the 'RAD51 paradox'.