Article
Cell Biology
Ilaria Ceppi, Elda Cannavo, Helene Bret, Rosa Camarillo, Francesca Vivalda, Roshan Singh Thakur, Amador Romero-Franco, Alessandro A. Sartori, Pablo Huertas, Raphael Guerois, Petr Cejka
Summary: In this study, the researchers used AlphaFold2 to identify a separation-of-function mutant of CtIP, CtIP-F728E-Y736E, which can still work with MRN but cannot stimulate ssDNA degradation by DNA2. The findings support a model in which the phosphorylation of CtIP by CDK activates DNA resection in the S phase, while the phosphorylation of CtIP by PLK1 disrupts its stimulation of DNA2, attenuating long-range resection later in the cell cycle.
GENES & DEVELOPMENT
(2023)
Article
Biology
Michael T. Kimble, Matthew J. Johnson, Mattie R. Nester, Lorraine S. Symington
Summary: Exo1 and Sgs1 are involved in long-range resection during HR, which is connected to the activation of the DNA damage checkpoint and the mobility of chromosomes.
Article
Biochemistry & Molecular Biology
Min Kyung Ju, Joo Rak Lee, Yeonsong Choi, Seon Young Park, Hee Jung Sul, Hee Jin Chung, Soyeong An, Semin Lee, Eunyoung Jung, Bohyun Kim, Bo Youn Choi, Bum Jun Kim, Hyeong Su Kim, Hyun Lim, Ho Suk Kang, Jae Seung Soh, Kyungjae Myung, Kab Choong Kim, Ji Woong Cho, Jinwon Seo, Tae Moon Kim, Ja Yil Lee, Yonghwan Kim, Hongtae Kim, Dae Young Zang
Summary: PWWP2B, one of the most frequently mutated genes in gastric adenocarcinoma, plays a role in DNA double-strand break repair by moving to sites of DNA damage through its interaction with UHRF1. It interacts with MRE11 and participates in homologous recombination by promoting DNA end-resection, facilitating DNA repair machinery recruitment and promoting HR-mediated DNA double-strand break repair.
Article
Multidisciplinary Sciences
Jinhua Han, Li Wan, Guixing Jiang, Liping Cao, Feiyu Xia, Tian Tian, Xiaomei Zhu, Mingjie Wu, Michael S. Y. Huen, Yi Wang, Ting Liu, Jun Huang
Summary: This study identifies a novel regulatory mechanism that modulates the activity of CtIP at DSBs and the extent of end resection through ATM-dependent sequential posttranslational modification of CtIP.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Donna R. Whelan, Eli Rothenberg
Summary: Using single-molecule localization super-resolution imaging assays, we observed the spatiotemporal behavior of key mediator and nuclease proteins during DNA resection at single-ended double-strand breaks. Multiple simultaneous resection events were demonstrated, with recruitment of various proteins and completion of resection 2 to 4 hours after break induction. Additionally, we identified potential roles of BRCA1 and BLM in homology search and repair resolution during HR.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Gaetana Sessa, Belen Gomez-Gonzalez, Sonia Silva, Carmen Perez-Calero, Romane Beaurepere, Sonia Barroso, Sylvain Martineau, Charlotte Martin, Asa Ehlen, Juan S. Martinez, Berangere Lombard, Damarys Loew, Stephan Vagner, Andres Aguilera, Aura Carreira
Summary: BRCA2-deficient cells accumulate DNA-RNA hybrids, and the BRCA2-DDX5 interaction helps in unwinding these structures, enhancing helicase activity and promoting repair of double-strand breaks.
Article
Biochemistry & Molecular Biology
Jae Jin Kim, Seo Yun Lee, Yiseul Hwang, Soyeon Kim, Jee Min Chung, Sangwook Park, Junghyun Yoon, Hansol Yun, Jae-Hoon Ji, Sunyoung Chae, Hyeseong Cho, Chan Gil Kim, Ted M. Dawson, Hongtae Kim, Valina L. Dawson, Ho Chul Kang
Summary: Mutual crosstalk among PAR, PARP1 metabolites, and DNA repair machinery is a key regulatory mechanism of DDR. USP39, identified as an inactive DUB associated with PAR-coupled DDR, localizes to DNA lesions in a PAR-dependent manner, regulating NHEJ and liquid demixing. Additionally, the USP39-associated spliceosome complex controls homologous recombination repair in a PAR-independent manner.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Cell Biology
Bo-Ruei Chen, Barry P. Sleckman
Summary: DNA double-strand breaks (DSBs) are constantly generated and repaired in cells, and the choice of repair pathway (homologous recombination or non-homologous end joining) depends on the structure of the broken DNA ends. Additionally, the chromatin state also affects the DNA end resection process.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Oncology
Waaqo Daddacha, Dominique Monroe, Kristen Carver, Edidiong R. Usoro, Ahmet Alptekin, Hongyan Xu, Satoru Osuka, Ali S. Arbab, Daitoku Sakamuro
Summary: Glioblastoma is a common and lethal primary brain tumor with limited treatment options. Depleting the SAMHD1 protein can enhance the sensitivity of glioblastoma to radiation and temozolomide, and viral protein X (Vpx) may serve as a therapeutic tool.
Article
Biochemistry & Molecular Biology
Seo-Yeon Jeong, Gurusamy Hariharasudhan, Min-Ji Kim, Ji-Yeon Lim, Sung Mi Jung, Eun-Ji Choi, In-Youb Chang, Younghoon Kee, Ho Jin You, Jung-Hee Lee
Summary: The research shows that the recruitment and functioning of CtIP are controlled by SIAH2 E3 ubiquitin ligase. Mutation of key lysine residues in CtIP impairs its recruitment and functioning, thereby affecting the DNA repair capacity of cells.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
John J. Skoko, Juxiang Cao, David Gaboriau, Myriam Attar, Alparslan Asan, Lisa Hong, Candice E. Paulsen, Hongqiang Ma, Yang Liu, Hanzhi Wu, Trey Harkness, Cristina M. Furdui, Yefim Manevich, Ciaran G. Morrison, Erika T. Brown, Daniel Normolle, Maria Spies, Michael Ashley Spies, Kate Carroll, Carola A. Neumann
Summary: This study identifies RAD51 Cys319 as a functionally significant site for the redox regulation of homologous recombination (HR) and cellular responses to ionizing radiation (IR). The loss of peroxiredoxin 1 (PRDX1) inhibits RAD51 focus formation and HR DNA repair, leading to increased DNA damage and sensitization of cells to irradiation.
Review
Cell Biology
Stephanie M. Ackerson, Carlan Romney, P. Logan Schuck, Jason A. Stewart
Summary: Regulation of DNA double-strand breaks and telomeres in cells is diametrically opposed, with DSBs requiring quick recognition and repair while telomeres must be protected to prevent unwanted chromosome fusions. Decision on whether to join DNA ends is critical for genome stability, and processing of telomeres and DSBs share commonalities. Repair of DSBs is determined by decision points that shift towards homologous recombination (HR) or non-homologous end joining (NHEJ).
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ethan J. Sanford, William J. Comstock, Vitor M. Faca, Stephanie C. Vega, Robert Gnugge, Lorraine S. Symington, Marcus B. Smolka
Summary: The Mec1/ATR kinase plays a crucial role in genome maintenance in response to genotoxic insults by promoting context-dependent signaling and DNA repair. This study highlights a distinct Mec1 signaling response triggered by hyper-resection, which influences the outcomes of DNA recombination.
Article
Cell Biology
Marta Llorens-Agost, Michael Ensminger, Hang Phuong Le, Anugrah Gawai, Jie Liu, Andres Cruz-Garcia, Sarita Bhetawal, Richard D. Wood, Wolf-Dietrich Heyer, Markus Loebrich
Summary: BRCA2-deficient cells are vulnerable to inactivation of DNA repair pathways for DSBs, which can be exploited clinically. RAD52 and BRCA2 regulate the TMEJ process by blocking the POL theta function, ensuring proper repair of DSBs in mitosis.
NATURE CELL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Tianpeng Zhang, Yashpal Rawal, Haoyang Jiang, Youngho Kwon, Patrick Sung, Roger A. Greenberg
Summary: Break-induced telomere synthesis (BITS) is a RAD51-independent mechanism that contributes to alternative lengthening of telomeres. This process utilizes a minimal replisome comprising PCNA and DNA polymerase-d to perform conservative DNA repair synthesis over long stretches. The response of this repair synthesis to complex secondary DNA structures and whether additional DNA repair events are orchestrated by the break-induced replisome remain unclear. In this study, the telomeric DNA damage response proteome during BITS was captured using a combination of synchronous double-strand break induction and proteomics of isolated chromatin segments (PICh). The findings revealed a replication stress-dominant response, with repair synthesis-driven DNA damage tolerance signaling through RAD18-dependent PCNA ubiquitination. The SNM1A nuclease was identified as the major effector of ubiquitinated PCNA-dependent DNA damage tolerance, playing a critical role in resection-dependent lesion bypass in mammalian cells.
Article
Immunology
Ayaka Sugiura, Gabriela Andrejeva, Kelsey Voss, Darren R. Heintzman, Xincheng Xu, Matthew Z. Madden, Xiang Ye, Katherine L. Beier, Nowrin U. Chowdhury, Melissa M. Wolf, Arissa C. Young, Dalton L. Greenwood, Allison E. Sewell, Shailesh K. Shahi, Samantha N. Freedman, Alanna M. Cameron, Patrik Foerch, Tim Bourne, Juan C. Garcia-Canaveras, John Karijolich, Dawn C. Newcomb, Ashutosh K. Mangalam, Joshua D. Rabinowitz, Jeffrey C. Rathmell
Summary: Antigenic stimulation promotes T cell metabolic reprogramming. The one-carbon metabolism enzyme MTHFD2 regulates purine synthesis and signaling in activated T cells. MTHFD2 deficiency reduces disease severity in multiple in vivo inflammatory disease models.
Article
Multidisciplinary Sciences
Roopesh Anand, Erika Buechelmaier, Ondrej Belan, Matthew Newton, Aleksandra Vancevska, Artur Kaczmarczyk, Tohru Takaki, David S. Rueda, Simon N. Powell, Simon J. Boulton
Summary: HELQ is a superfamily 2 helicase with 3' to 5' polarity, and disruption in mice causes germ cells loss, infertility, and increased predisposition to ovarian and pituitary tumors. Defects in HELQ result in cellular hypersensitivity to cisplatin and mitomycin C, as well as persistence of RAD51 foci after DNA damage. HELQ possesses an intrinsic ability to capture RPA-bound DNA strands and facilitate annealing of complementary sequences.
Article
Oncology
Evan B. Glass, Alyssa A. Hoover, Kennady K. Bullock, Matthew Z. Madden, Bradley Reinfeld, Whitney Harris, Dominique Parker, Demetra H. Hufnagel, Marta A. Crispens, Dineo Khabele, W. Kimryn Rathmell, Jeffrey C. Rathmell, Andrew J. Wilson, Todd D. Giorgio, Fiona E. Yull
Summary: The study demonstrated a potential therapeutic effect in mouse models of ovarian cancer by repolarizing ovarian TAMs using IkB alpha-loaded MnNPs, including stimulation of NF-kB activity, re-polarization to M1 macrophages, and reduced tumor burden.
Article
Cardiac & Cardiovascular Systems
Jingjing Zheng, Holly C. Dooge, Marta Perez-Hernandez, Yan-Ting Zhao, Xi Chen, Jonathan J. Hernandez, Carmen R. Valdivia, Julieta Palomeque, Eli Rothenberg, Mario Delmar, Hector H. Valdivia, Francisco J. Alvarado
Summary: RyR2 is a crucial protein in the heart that regulates the release of Ca2+. This study found that a decrease in RyR2 expression has limited impact on overall cardiac function, highlighting the redundancy of RyR2 protein expression and the plasticity of the excitation-contraction coupling apparatus.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2022)
Article
Cell Biology
PamelaSara E. Head, Sangho Myung, Yong Chen, Jessica L. Schneller, Cindy Wang, Nicholas Duncan, Pauline Hoffman, David Chang, Abigael Gebremariam, Marjan Gucek, Irini Manoli, Charles P. Venditti
Summary: Organic acidemias like methylmalonic acidemia (MMA) are genetic metabolic disorders caused by defects in the breakdown of amino and fatty acids. This study discovered a widespread posttranslational modification called methylmalonylation that inhibits enzymes in the urea cycle and glycine cleavage pathway in MMA. The researchers found that SIRT5 controls the metabolism of these posttranslational modifications. Gene therapy using modified SIRT5 improved symptoms of MMA in mice.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Multidisciplinary Sciences
Kate E. Coleman, Yandong Yin, Sarah Kit Leng Lui, Sarah Keegan, David Fenyo, Duncan J. Smith, Eli Rothenberg, Tony T. Huang
Summary: This study provides mechanistic insights into how auto-cleavage of the USP1 deubiquitinase regulates DNA replication and genome stability, and discusses the implications for cancer therapy by targeting USP1 activity via protein-DNA trapping.
NATURE COMMUNICATIONS
(2022)
Review
Cell Biology
Shaun M. Christie, Carel Fijen, Eli Rothenberg
Summary: V(D)J recombination is a crucial mechanism in the adaptive immune system, generating diverse antigen receptors. This review focuses on the regulatory functions of RAGs, recruitment of RAGs and formation of paired complexes, transition from post-cleavage complex to repair phase, and redundant roles of certain factors in break repair. Understanding these processes is important for avoiding off-target recombination or deficiency-mediated clinical manifestations.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Cell Biology
E. Werner, A. Gokhale, M. Ackert, C. Xu, Z. Wen, A. M. Roberts, B. R. Roberts, A. Vrailas-Mortimer, A. Crocker, V Faundez
Summary: By studying genetic cellular models, we found that manganese exposure compromises the function and composition of mitochondrial RNA granules, leading to disruption of mitochondrial transcript processing and respiratory chain function. Interestingly, impaired RNA granule function acts as a protective mechanism against acute manganese toxicity.
MOLECULAR BIOLOGY OF THE CELL
(2022)
Article
Biochemistry & Molecular Biology
Swagata Halder, Aurore Sanchez, Lepakshi Ranjha, Giordano Reginato, Ilaria Ceppi, Ananya Acharya, Roopesh Anand, Petr Cejka
Summary: RAD51 and BRCA2 play critical roles in DNA repair and protection. RAD51 binds to single-stranded DNA for its recombination function, but binding to double-stranded DNA is inhibitory. Surprisingly, we found that the protective function of RAD51 actually depends on its binding to double-stranded DNA. The BRC4 repeat of BRCA2 disrupts RAD51 binding to double-stranded DNA and impairs its protective function. However, the C-terminal RAD51-binding segment (TR2) of BRCA2 overcomes the inhibitory effect of BRC4 and stabilizes RAD51 binding to double-stranded DNA, promoting DNA protection.
Article
Astronomy & Astrophysics
Nolan E. Hertel, Steven R. Biegalski, Victoria I. Nelson, William A. Nelson, Sharmistha Mukhopadhyay, Zitong Su, Alexis M. Chan, Aparna H. Kesarwala, William S. Dynan
Summary: This study explores a different approach to provide a high-LET radiation field for space radiation countermeasure discovery, based on the use of compact portable sources to generate neutron-induced charged particles. Modeling studies and experimental validation demonstrate the feasibility of this approach. However, the neutron approach still has some limitations.
LIFE SCIENCES IN SPACE RESEARCH
(2022)
Review
Endocrinology & Metabolism
PamelaSara E. Head, Jordan L. Meier, Charles P. Venditti
Summary: Methylmalonic acidemia (MMA) is a severe inborn error of metabolism with limited treatment options. Aberrant acylation has been identified as a characteristic feature of MMA, suggesting that targeting posttranslational modifications may be a new therapeutic approach.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Article
Immunology
Lihong Wang-Bishop, Blaise R. Kimmel, Verra M. Ngwa, Matthew Z. Madden, Jessalyn J. Baljon, David C. Florian, Ann Hanna, Lucinda E. Pastora, Taylor L. Sheehy, Alexander J. Kwiatkowski, Mohamed Wehbe, Xiaona Wen, Kyle W. Becker, Kyle M. Garland, Jacob A. Schulman, Daniel Shae, Deanna Edwards, Melissa M. Wolf, Rossane Delapp, Plamen P. Christov, Kathryn E. Beckermann, Justin M. Balko, W. Kimryn Rathmel, Jeffrey C. Rathmell, Jin Chen, John T. Wilson
Summary: The tumor-associated vasculature presents obstacles for T cell infiltration and effective tumor control. The activation of the STING pathway is associated with T cell infiltration in human cancers. Therefore, STING-activating nanoparticles (STANs) were evaluated for their effect on the tumor vasculature and T cell infiltration. In mouse tumor models, intravenous administration of STANs promoted vascular normalization, resulting in improved T cell infiltration and antitumor function.
SCIENCE IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Antonia Kefala Stavridi, Amandine Gontier, Vincent Morin, Philippe Frit, Virginie Ropars, Nadia Barboule, Carine Racca, Sagun Jonchhe, Michael J. Morten, Jessica Andreani, Alexey Rak, Pierre Legrand, Alexa Bourand-Plantefol, Steven W. Hardwick, Dimitri Y. Chirgadze, Paul Davey, Taiana Maia De Oliveira, Eli Rothenberg, Sebastien Britton, Patrick Calsou, Tom L. Blundell, Paloma F. Varela, Amanda K. Chaplin, Jean-Baptiste Charbonnier
Summary: This study reveals the molecular mechanism by which the interaction between the Ku70-Ku80 heterodimer and inositol-hexaphosphate (IP6) enhances the activity of classical Non-Homologous End Joining (c-NHEJ) pathway for DNA repair.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Aina Maria Mas, Enrique Goni, Igor Ruiz de los Mozos, Aida Arcas, Luisa Statello, Jovanna Gonzalez, Lorea Blazquez, Wei Ting Chelsea Lee, Dipika Gupta, Alvaro Sejas, Shoko Hoshina, Alexandros Armaos, Gian Gaetano Tartaglia, Shou Waga, Jernej Ule, Eli Rothenberg, Maria Gomez, Maite Huarte
Summary: In this study, the authors demonstrate that ORC1, a subunit of the Origin Recognition Complex, interacts with RNAs transcribed from genes with origins of replication at their TSSs, and this interaction positively correlates with origin activation. They show that the binding of RNA to ORC1 facilitates chromatin release and activation of proximal origins, and this process is regulated by phosphorylation and degradation. These findings reveal a novel non-coding function of RNA in coordinating the activation of replication origins.
NATURE COMMUNICATIONS
(2023)
Article
Biochemical Research Methods
Alicia Lane, Avanti Gokhale, Erica Werner, Anne Roberts, Amanda Freeman, Blaine Roberts, Victor Faundez
Summary: This protocol describes how to use ICP-MS to quantitatively analyze metals, sulfur, and phosphorus in biological specimens. It achieves absolute quantification using standard curves and reduces variability through sulfur or phosphorus standardization. This protocol is valuable for overcoming challenges due to limited sample amounts and for facilitating studies on the biological roles of metals in health and disease.
