Review
Biochemistry & Molecular Biology
Elias A. Tannous, Peter M. Burgers
Summary: DNA replication is a precise process, but cells face obstacles such as replication blocks and lack of precursors that can lead to chromosome instability and mutations. The PIKK family plays a crucial role in the cell's response mechanism, with recent studies showing significant progress in understanding the structure and activity of human ATR and ATM.
CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Verena Hurst, Kiran Challa, Felix Jonas, Romain Forey, Ragna Sack, Jan Seebacher, Christoph D. Schmid, Naama Barkai, Kenji Shimada, Susan M. Gasser, Jerome Poli
Summary: In budding yeast, the Mec1 kinase plays a crucial role in evicting RNAPII and RNAPIII to facilitate replication fork progression. The non-phosphorylatable mec1-S1991A mutant hinders replication fork progression and compromises survival on hydroxyurea. Disrupting chromatin-bound RNAPII can alleviate the lethality in mec1-S1991A mutants.
Article
Biochemistry & Molecular Biology
Richard He, Zhiguo Zhang
Summary: DNA replication stress can disrupt normal DNA synthesis. In this article, the authors used specific sequencing technologies to study DNA synthesis in response to replication stress. They found that a protein called Rad53 can regulate DNA synthesis on both leading and lagging strands, thereby maintaining genome integrity.
Article
Biochemistry & Molecular Biology
Elias A. Tannous, Luke A. Yates, Xiaodong Zhang, Peter M. Burgers
Summary: A mutation in Mec1 leading to constitutive activity was identified, and structural analysis revealed the molecular basis for Mec1 activation and key regulatory mechanisms through conformational changes.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2021)
Article
Biology
Erik Waskiewicz, Michalis Vasiliou, Isaac Corcoles-Saez, Rita S. Cha
Summary: Through data mining and functional genetic analysis, the study identified functionally important and evolutionarily conserved residues in ATM/ATR, shedding light on their diverse roles in enzyme functions. The findings suggest that loss of intrinsic kinase activity in ATM/ATR is infrequent in carcinogenesis.
COMMUNICATIONS BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Vaughn Thada, David Cortez
Summary: TOPBP1 and ETAA1 are two activators of ATR, which activate ATR through the same biochemical mechanism. Dimerization of both TOPBP1 and ETAA1 is crucial for optimal ATR signaling and genome stability.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Review
Cell Biology
Carlo Rinaldi, Paolo Pizzul, Maria Pia Longhese, Diego Bonetti
Summary: DNA transcription and replication are essential physiological processes, but they can pose a threat to genome integrity when competing for the same DNA substrate. R-loop structures can play important roles in normal physiological functions, but may lead to DNA damage and genome instability when their homeostasis is altered. Research has made progress in understanding R-loop regulation, but more studies are needed to fully comprehend their impact on genome stability and the cellular response to their formation.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Anastasia Ricci, Federica Biancucci, Gianluca Morganti, Mauro Magnani, Michele Menotta
Summary: Ataxia Telangiectasia (AT) is a rare neurodegenerative disease caused by biallelic mutations in the ataxia telangiectasia mutated gene. Administration of dexamethasone through autologous erythrocytes has shown positive effects on neurologic features in AT patients. New ATM variants, found in AT patients treated with dexamethasone, have the ability to rescue ATM activity in AT cells and regulate cellular physiological functions. The in silico designed ATM variant may be used for the treatment of AT patients.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Review
Genetics & Heredity
Tai-Ting Woo, Chi-Ning Chuang, Ting-Fang Wang
Summary: Rad51, a central player in homologous recombination, is finely tuned by posttranslational modifications conducted by multiple protein kinases to maintain DNA integrity. Phosphorylation by different kinases regulates Rad51 stability, promoting DNA repair and recombination while also participating in protein homeostasis.
Article
Biochemistry & Molecular Biology
Sara Ovejero, Sylvain Kumanski, Caroline Soulet, Julie Azarli, Benjamin Pardo, Olivier Santt, Angelos Constantinou, Philippe Pasero, Maria Moriel-Carretero
Summary: Upon DNA damage, cells activate the DNA damage response to coordinate proliferation and DNA repair. Lipids have the potential to convey signals that modulate DNA surveillance and repair, although the underlying mechanisms are poorly understood. In this study, we found that the number of lipid droplets specifically increased in response to DNA breaks. We demonstrated that the storage of sterols in these droplets stabilizes phosphatidylinositol-4-phosphate (PI(4)P) at the Golgi, which binds to the DDR kinase ATM and attenuates the initial nuclear ATM-driven response to DNA breaks. This finding has important implications for addressing genetic instability pathologies through dietary and pharmacological interventions.
Review
Biochemistry & Molecular Biology
Jinal A. Patel, Hyungjin Kim
Summary: Accurate replication of the genome is crucial for cellular survival and tumor prevention. The DNA replication fork is susceptible to DNA lesions and damages that hinder its progression, leading to genome instability and tumorigenesis. The fork protection complex (FPC), particularly TIMELESS (TIM), plays a vital role in safeguarding the integrity of both active and stalled replication forks. Understanding TIM's multifaceted functions in DNA replication and stalled fork protection, as well as its collaboration with other genome surveillance factors, provides insights for potential therapies targeting replication vulnerability in cancer cells.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Virology
Andrew P. P. Kurland, Boris Bonaventure, Jeffrey R. R. Johnson
Summary: In this study, we identified kinases that regulate innate immune pathways by conducting a small-scale kinase inhibitor screen and quantitative proteomics analysis. We found that inhibitors of ATM, ATR, AMPK, and PLK1 reduced interferon-stimulated gene expression in response to poly(I:C)-induced activation of innate immune pathways. However, RNA interference experiments did not validate these findings, suggesting off-target effects of the inhibitors. Mapping the effects of kinase inhibitors on various stages of innate immune pathways may reveal novel mechanisms of pathway control.
Article
Oncology
Nicola Lockwood, Silvia Martini, Ainara Lopez-Pardo, Katharina Deiss, Hendrika A. Segeren, Robert K. Semple, Ian Collins, Dimitra Repana, Mathias Cobbaut, Tanya Soliman, Francesca Ciccarelli, Peter J. Parker
Summary: G2 arrest is crucial for the faithful segregation of sister chromatids, and the p53-p21 signaling pathway plays an essential role in cell lines, patient-derived cells, and colorectal cancer organoids. In arrest-defective hTERT-positive cells, the PKC epsilon failsafe mechanism is engaged. In ALT-dependent cancer cells, a distinct form of p53-independent G2 arrest is mediated by BLM and Chk1.
Article
Biochemistry & Molecular Biology
Jialu Shao, Lei Huang, Wenwen Lai, Yi Zou, Qihua Zhu
Summary: ATR, a crucial member of the PIKK family, plays a vital role in the DNA damage response. Tumor cells with DDR dysfunction or ATM gene defects are more reliant on ATR for survival, making it an attractive anticancer drug target based on synthetic lethality. A potent and highly selective ATR inhibitor, ZH-12 (IC50 = 0.0068 mu M), demonstrated potent antitumor activity alone or in combination with cisplatin in a xenograft mouse model of human colorectal adenocarcinoma. Overall, ZH-12 appears to be a promising ATR inhibitor based on the principle of synthetic lethality and warrants further in-depth investigation.
Review
Oncology
Congqi Shi, Kaiyu Qin, Anqi Lin, Aimin Jiang, Quan Cheng, Zaoqu Liu, Jian Zhang, Peng Luo
Summary: This study summarizes currently identified and promising biomarkers for predicting the response of oncology patients to immune checkpoint inhibitors, and explores the mechanism of combination therapy with immune checkpoint inhibitors and DNA damage repair inhibitors.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)
Article
Cell Biology
Jan Padeken, Stephen Methot, Peter Zeller, Colin E. Delaney, Veronique Kalck, Susan M. Gasser
Summary: The study shows that the histone methyltransferase SET-25 in C. elegans can establish repressed chromatin domains, silencing novel insertions of transposons and tissue-specific genes during development. Two redundant pathways recruit SET-25 to its targets, with one pathway involving LIN-61 and MET-2, and the other pathway involving NRDE-3 and small RNAs, primarily targeting conserved transposons. The loss of these pathways results in the derepression of transposons in embryos, leading to increased embryonic lethality.
GENES & DEVELOPMENT
(2021)
Editorial Material
Cell Biology
Susan M. Gasser, Gerd A. Blobel
CURRENT OPINION IN GENETICS & DEVELOPMENT
(2021)
Correction
Multidisciplinary Sciences
Nikolaus Rajewsky, Genevieve Almouzni, Stanislaw A. Gorski, Stein Aerts, Ido Amit, Michela G. Bertero, Christoph Bock, Annelien L. Bredenoord, Giacomo Cavalli, Susanna Chiocca, Hans Clevers, Bart De Strooper, Angelika Eggert, Jan Ellenberg, Xose M. Fernandez, Marek Figlerowicz, Susan M. Gasser, Norbert Hubner, Jorgen Kjems, Jurgen A. Knoblich, Grietje Krabbe, Peter Lichter, Sten Linnarsson, Jean-Christophe Marine, John C. Marioni, Marc A. Marti-Renom, Mihai G. Netea, Dorthe Nickel, Marcelo Nollmann, Halina R. Novak, Helen Parkinson, Stefano Piccolo, Ines Pinheiro, Ana Pombo, Christian Popp, Wolf Reik, Sergio Roman-Roman, Philip Rosenstiel, Joachim L. Schultze, Oliver Stegle, Amos Tanay, Giuseppe Testa, Dimitris Thanos, Fabian J. Theis, Maria-Elena Torres-Padilla, Alfonso Valencia, Celine Vallot, Alexander van Oudenaarden, Marie Vidal, Thierry Voet
Article
Biology
Kenji Shimada, Monika Tsai-Pflugfelder, Niloofar Davoodi Vijeh Motlagh, Neda Delgoshaie, Jeannette Fuchs, Heinz Gut, Susan M. Gasser
Summary: The study investigates mutations in the Pol31 segment of DNA polymerase delta, identifying substitutions that can restore deficiencies in pol32 Delta cells. These mutations not only affect DNA replication and repair processes but also impact recovery from pathways such as hydroxyurea, break-induced replication, and trans-lesion synthesis repair.
LIFE SCIENCE ALLIANCE
(2021)
Article
Biochemistry & Molecular Biology
Verena Hurst, Kiran Challa, Felix Jonas, Romain Forey, Ragna Sack, Jan Seebacher, Christoph D. Schmid, Naama Barkai, Kenji Shimada, Susan M. Gasser, Jerome Poli
Summary: In budding yeast, the Mec1 kinase plays a crucial role in evicting RNAPII and RNAPIII to facilitate replication fork progression. The non-phosphorylatable mec1-S1991A mutant hinders replication fork progression and compromises survival on hydroxyurea. Disrupting chromatin-bound RNAPII can alleviate the lethality in mec1-S1991A mutants.
Article
Cell Biology
Verena Hurst, Kiran Challa, Kenji Shimada, Susan M. Gasser
Summary: DNA damage induced by 405-nm laser light recruits proteins involved in base excision repair (BER), but perturbing actin or tubulin polymerization in human cells alters the dynamics of BER factors. Depolymerization of cytoplasmic actin may compromise BER efficiency in mammals due to increased levels of nuclear actin and tubulin, linking cytoskeletal integrity to BER.
MOLECULAR BIOLOGY OF THE CELL
(2021)
Article
Cell Biology
Stephen P. Methot, Jan Padeken, Giovanna Brancati, Peter Zeller, Colin E. Delaney, Dimos Gaidatzis, Hubertus Kohler, Alexander van Oudenaarden, Helge Grosshans, Susan M. Gasser
Summary: The deposition of H3K9me2 and H3K9me3 can repress lineage-specific and germline genes in terminally differentiated Caenorhabditis elegans tissues by restricting the activity of specific transcription factors. Changes in H3K9me during development affect gene regulation and the maintenance of cellular functions.
NATURE CELL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Colin E. Delaney, Stephen P. Methot, Veronique Kala, Jan Seebacher, Daniel Hess, Susan M. Gasser, Jan Padeken
Summary: Genetic and genome-wide analysis of the SETDB1-like enzyme MET-2 in Caenorhabditis elegans reveals its role in promoting transcriptional silencing and fertility through both H3K9 methylation and focus formation. MET-2 has a noncatalytic function that contributes to gene repression. In normal development, MET-2 activity helps maintain fertility, while under heat stress, MET-2 foci disperse, resulting in increased acetylation and transcriptional derepression.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)
Review
Cell Biology
Jan Padeken, Stephen P. Methot, Susan M. Gasser
Summary: Heterochromatin is characterized by histone H3 Lys9 methylation, which ensures transcriptional silencing of repetitive elements and genes. The methyltransferases and "readers" of H3K9me2 or H3K9me3 are highly conserved and show redundancy. Loss or mistargeting of individual H3K9 methyltransferases can lead to impaired cell differentiation, loss of tissue identity, premature aging, and/or cancer. Recent studies in mammals have shed light on the roles of H3K9-specific histone methyltransferases in transcriptional homeostasis during tissue differentiation.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2022)
Correction
Biochemistry & Molecular Biology
Colin E. Delaney, Stephen P. Methot, Veronique Kalck, Jan Seebacher, Daniel Hess, Susan M. Gasser, Jan Padeken
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)
Editorial Material
Genetics & Heredity
Susan M. Gasser
Summary: In this interview, Professor Susan Gasser discusses her research on genome stability, epigenetic regulation, and chromatin organization, as well as her efforts in supporting women in research. She has made significant contributions to the field of chromatin structure and has been recognized with numerous awards and honors. She continues to actively promote the careers of women scientists in Europe and Japan.
Editorial Material
Biochemistry & Molecular Biology
Marta Rodriguez-Martinez, Jens Nielsen, Sam Dupont, Jessica Vamathevan, Beverley J. Glover, Lindsey C. Crosswell, Brendan Rouse, Ben F. Luisi, Chris Bowler, Susan M. Gasser, Detlev Arendt, Tobias J. Erb, Victor de Lorenzo, Edith Heard, Kiran Raosaheb Patil
Summary: Molecular biology has great potential in addressing climate change and biodiversity loss, but it is currently not well incorporated into strategies. We call for a community-wide action to bring molecular biology to the forefront of climate change solutions.
Review
Biochemistry & Molecular Biology
Susan M. Gasser, Francoise Stutz
Summary: The covalent linkage of Ubiquitin and SUMO to lysine residues plays important roles in DNA repair pathway choice and transcription regulation. SUMOylation mainly affects cellular processes by relocalizing modified proteins, particularly in response to DNA damage.
Editorial Material
Cell Biology
Susan M. M. Gasser
Summary: The compact state of chromatin induced by methylation of H3K9 on histone H3 is believed to be involved in heritable transcriptional repression. A recent study reveals that transient deposition of H3K9me3 helps stabilize stalled DNA replication forks, while its reversal allows for accurate fork restart.
NATURE CELL BIOLOGY
(2023)
Article
Biochemical Research Methods
Kiran Challa, Jan Seebacher, Susan M. Gasser
Summary: This study presents a fractionation protocol optimized for quantifying changes in the chromatin-bound proteome using tandem mass tag multiplexing-based tandem mass spectrometry. The protocol has been successfully applied to yeast cells to characterize changes induced by exposure to DNA-damaging drugs. Detailed steps for stringent chromatin fractionation, sample preparation for mass spectrometry, and evaluation are provided in the protocol.
