Article
Hematology
Yusuke Okamoto, Masako Abe, Anfeng Mu, Yasuko Tempaku, Colette B. Rogers, Ayako L. Mochizuki, Yoko Katsuki, Masato T. Kanemaki, Akifumi Takaori-Kondo, Alexandra Sobeck, Anja-Katrin Bielinsky, Minoru Takata
Summary: Fanconi anemia (FA) is a hereditary disorder caused by mutations in any 1 of 22 FA genes. Recent studies have shown that the DNA/RNA helicase SLFN11 plays a role in cell death sensitivity to chemotherapeutic treatments in cancer cells. The depletion of SLFN11 has been shown to improve cell survival in FA patient-derived cells, suggesting a potential link between SLFN11 and FA pathophysiology.
Article
Multidisciplinary Sciences
Ann-Marie K. Shorrocks, Samuel E. Jones, Kaima Tsukada, Carl A. Morrow, Zoulikha Belblidia, Johanna Shen, Iolanda Vendrell, Roman Fischer, Benedikt M. Kessler, Andrew N. Blackford
Summary: The study reveals that the BTR complex contains multiple conserved motifs that interact cooperatively with the single-stranded DNA-binding protein RPA, facilitating BLM recruitment to stalled replication forks for promoting their restart after replication stress.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Arik Townsend, Gabriella Lora, Justin Engel, Neysha Tirado-Class, Huzefa Dungrawala
Summary: DCAF14, a substrate receptor for the CRL4 complex, plays a crucial role in stabilizing stalled replication forks and preventing double-strand breaks, thereby promoting genome integrity. This study demonstrates the replication stress response functions of DCAF14 in ensuring genome maintenance.
Review
Biochemistry & Molecular Biology
Longfu Xu, Matthew T. J. Halma, Gijs J. L. Wuite
Summary: Single-stranded DNA-binding proteins (SSBs) are essential for DNA metabolism and play crucial roles in maintaining genome integrity and coordinating with other proteins involved in DNA replication, recombination, and repair. Recent advances in single-molecule techniques and structural methods have greatly improved our understanding of the binding dynamics and interaction of SSBs with ssDNA and other protein partners. We highlight the central coordination role of SSBs in directly modulating the activities of other proteins and discuss the various modes of interaction between SSBs and their protein partners, providing a comprehensive view of the interaction network shaped by SSBs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
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
Biochemistry & Molecular Biology
Nicole M. Hoitsma, Jessica Norris, Thu H. Khoang, Vikas Kaushik, Rahul Chadda, Edwin Antony, Mark Hedglin, Bret D. Freudenthal
Summary: APE1 plays a significant role in DNA replication by cleaving abasic sites in single-stranded DNA, generating double strand breaks that could collapse the replication fork. This study provides molecular insights into APE1 activity on abasic substrates resembling stalled replication forks or gaps and reveals the interplay between APE1 and RPA.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biology
Deepak Bhat, Samuel Hauf, Charles Plessy, Yohei Yokobayashi, Simone Pigolotti, Armita Nourmohammad
Summary: In this study, a new method was proposed to infer the dynamics of Replisomes from DNA abundance distribution. The method was applied to measure the DNA abundance distribution in Escherichia coli populations growing at different temperatures. The results showed that the speed of Replisomes increases with temperature and exhibits wave-like variations along the genome, which correlates with the variation of mutation rate. This study provides insights into the replication dynamics of bacteria.
Article
Biochemistry & Molecular Biology
Arvind Panday, Nicholas A. Willis, Rajula Elango, Francesca Menghi, Erin E. Duffey, Edison T. Liu, Ralph Scully
Summary: The study reveals that the FANCM gene encodes a multi-domain scaffolding and motor protein that regulates repair pathway choice at stalled replication forks, and its ATPase function may be a promising target for therapy of BRCA1-linked cancer.
Review
Biochemistry & Molecular Biology
Jun-Tao Guo, Fareeha Malik
Summary: Single-stranded DNA binding proteins (SSBs) play critical roles in maintaining genome stability and transcriptional regulation, and machine learning-based approaches have been developed for predicting SSBs from double-stranded DNA binding proteins (DSBs).
Article
Biochemistry & Molecular Biology
Archana Krishnamoorthy, Jessica Jackson, Taha Mohamed, Madison Adolph, Alessandro Vindigni, David Cortez
Summary: RAD51 facilitates replication fork reversal and RADX can either inhibit or promote fork reversal depending on replication stress levels. RADX interacts directly with RAD51 and single-strand DNA to confine fork reversal to persistently stalled forks, preventing genome instability.
Review
Oncology
Sui Par, Sofia Vaides, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Jason Stewart, John J. Turchi
Summary: The OB-fold motif plays a critical role in chromosome maintenance and stability, enabling sequence-independent binding to single-stranded DNA. Proteins containing OB-fold are essential for genome stability pathways, facilitating protein-DNA interactions and catalyzing DNA replication, repair, and recombination. Targeting OB-fold containing proteins shows promise in cancer therapy by disrupting critical protein-DNA interactions, with potential for expanding opportunities for more effective cancer treatment through the development of agents targeting OB-folds.
Article
Multidisciplinary Sciences
Kanika Jain, Tyler H. Stanage, Elizabeth A. Wood, Michael M. Cox
Summary: Deletion of the entire gene encoding the RarA protein in Escherichia coli leads to growth defects and additional deficiencies. However, it was later discovered that most of these effects are actually due to sequences in the rarA gene that affect the expression of the downstream gene, serS.
Article
Cell Biology
Qi Zhang, Rongjiao Hao, Hongxia Chen, Gangqiao Zhou
Summary: In this study, it was demonstrated that SOSSB1 and SOSSB2 positively regulate HR repair and their mutual expression is mutually regulated through their competitive binding with SOSSA. The destabilized SOSSB1 and SOSSB2 proteins can be degraded via the proteasome pathway. Additionally, the simultaneous loss of SOSSB1 and SOSSB2 aggravates homologous recombination-mediated DNA repair defects, enhances cellular radiosensitivity and promotes cell apoptosis.
CELL DEATH DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Xinxing Lyu, Kai-Hang Lei, Pau Biak Sang, Olga Shiva, Megan Chastain, Peter Chi, Weihang Chai
Summary: The CST complex protects stalled replication forks from degradation by the MRE11 nuclease by inhibiting MRE11 binding to reversed forks, thus preventing excessive nascent-strand degradation and preserving genome integrity under replication stress, particularly in BRCA2 deficient cells.
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
Immunology
Arutha Kulasinghe, Ning Liu, Chin Wee Tan, James Monkman, Jane E. Sinclair, Dharmesh D. Bhuva, David Godbolt, Liuliu Pan, Andy Nam, Habib Sadeghirad, Kei Sato, Gianluigi Li Bassi, Ken O'Byrne, Camila Hartmann, Anna Flavia Ribeiro Dos Santos Miggiolaro, Gustavo Lenci Marques, Lidia Zytynski Moura, Derek Richard, Mark Adams, Lucia de Noronha, Cristina Pellegrino Baena, Jacky Y. Suen, Rakesh Arora, Gabrielle T. Belz, Kirsty R. Short, Melissa J. Davis, Fernando Souza-Fonseca Guimaraes, John F. Fraser
Summary: The study reveals distinct transcriptomic profiles in cardiac tissues of SARS-CoV-2 and pH1N1 influenza infection, with upregulation of genes associated with DNA damage and repair, heat shock, and macrophage infiltration in COVID-19 patients' cardiac tissues. In comparison, pH1N1 infection showed upregulation of interferon and complement pathways. This highlights the need for further understanding of the effects on extra-pulmonary organs, including the cardiovascular system, in COVID-19 patients.
Article
Cell Biology
Melanie Young, Ming Tang, Huika Li, Derek J. Richard, Donald S. A. McLeod, Michael C. d'Emden, Kerry Richard
Summary: Preeclampsia is a life-threatening condition caused by poor placentation during pregnancy. The study suggests that transthyretin, a thyroid hormone binding protein, binds to soluble endoglin (sEng) and enhances its uptake by hepatocytes. This finding may lead to potential treatment options for reducing sEng-induced vascular dysfunction.
MOLECULAR AND CELLULAR ENDOCRINOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Tabassum Khair Barbhuiya, Mark Fisher, Eric D. Boittier, Emma Bolderson, Kenneth J. O'Byrne, Derek J. Richard, Mark Nathaniel Adams, Neha S. Gandhi
Summary: The study investigates the mechanism of CDCA3 binding to APC/C-Cdh1 through the non-canonical ABBA-like motif. The research finds that H-bonds, hydrophobic and ionic interactions within the ABBA-like motif are crucial for the binding. Alanine mutations disrupt the structure of the linker region, leading to altered affinities and binding to alternate sites on Cdh1.
Article
Chemistry, Organic
Luke R. Odell, Bobo Skillinghaug, Christof Matt, Peng Wu, Tobias Koolmeister, Matthieu Desroses, Sabin Llona-Minguez, Olov Wallner, Thomas Helleday, Martin Scobie
Summary: Here, we describe the development of a new cascade reaction for the synthesis of rare indazole acetic acid scaffolds. By heating 3-amino-3-(2-nitroaryl)propanoic acids with an appropriate nucleophile/solvent under basic conditions, three distinct indazole acetic acid derivatives (unsubstituted, hydroxy, and alkoxy) can be conveniently synthesized. The reaction can tolerate various functional groups and electronic effects, resulting in the synthesis and characterization of 23 novel indazole acetic acids. This work provides a valuable synthetic strategy for drug discovery programs.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Melanie Walter, Florian Mayr, Bishoy M. F. Hanna, Victoria Cookson, Oliver Mortusewicz, Thomas Helleday, Patrick Herr
Summary: NUD22 enzyme converts UDP-glucose into glucose-1-phosphate and uridine monophosphate. This study reveals that NUD22 is crucial for maintaining cancer cell growth and preventing replication stress. High expression of NUD22 is correlated with worse survival outcomes in patients, indicating its potential as a target for cancer therapy.
Article
Endocrinology & Metabolism
Mark N. Adams, Laura V. Croft, Aaron Urquhart, Mohamed Ashick Mohamed Saleem, Anja Rockstroh, Pascal H. G. Duijf, Patrick B. Thomas, Genevieve P. Ferguson, Idris Mohd Najib, Esha T. T. Shah, Emma Bolderson, Shivashankar Nagaraj, Elizabeth D. Williams, Colleen C. Nelson, Kenneth J. O'Byrne, Derek J. Richard
Summary: This study evaluated the role of hSSB1/NABP2 in modulating the cellular response to androgens and ionizing radiation in prostate cancer. The expression of hSSB1 in prostate cancer is correlated with genomic instability and it regulates pathways involved in cell cycle progression and transcription. Additionally, hSSB1 is involved in modulating androgen response through transcriptional regulation. Exploiting hSSB1 in prostate cancer treatment might improve patient outcomes in ADT and/or radiotherapy.
Article
Immunology
Zachariah P. Schuurs, John P. McDonald, Laura V. Croft, Derek J. Richard, Roger Woodgate, Neha S. Gandhi
Summary: This study focuses on the issue of antibiotic resistance and explores the structure and function of LexA protein to find small molecule inhibitors that can inhibit its degradation. The research reveals that a specific covalent inhibitor can react with the Ser-119 residue in LexA protein, thus inhibiting the SOS response. This study provides a starting point for future research on preventing antibiotic resistance.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2023)
Article
Oncology
Ming Tang, Joshua T. Burgess, Mark Fisher, Didier Boucher, Emma Bolderson, Neha S. Gandhi, Kenneth J. O'Byrne, Derek J. Richard, Amila Suraweera
Summary: This study aimed to explore the binding pose of COMMD4-H2B and develop a H2B peptide that disrupts the COMMD4-H2B interaction, which could serve as a potential therapeutic target for non-small cell lung cancer (NSCLC).
BRITISH JOURNAL OF CANCER
(2023)
Article
Biochemistry & Molecular Biology
Serene El-Kamand, Mark N. Adams, Jacqueline M. Matthews, Mar-Dean Du Plessis, Ben Crossett, Angela Connolly, Natasha Breen, Alexander Dudley, Derek J. Richard, Roland Gamsjaeger, Liza Cubeddu
Summary: In this study, a combined approach of in silico, biochemical, and functional experiments was used to uncover the molecular details of INTS3 binding to Nbs1. The forkhead-associated domain of Nbs1 was found to interact with INTS3 via phosphorylation-dependent binding to INTS3 at Threonine 592, with contributions from Serine 590. Based on these data, a model of MRN recruitment to a double-strand DNA break via INTS3 was proposed.
Article
Chemistry, Physical
Ming Tang, Amila Suraweera, Xuqiang Nie, Zilin Li, Pinglin Lai, James W. Wells, Kenneth J. O'Byrne, Robert J. Woods, Emma Bolderson, Derek J. Richard
Summary: In this study, the atomic-level mechanisms of Banf1-DNA binding and the effects of mono- and di-phosphorylation on Banf1's DNA-binding capability were explored using molecular modelling and dynamics simulations. It was found that mono-phosphorylation induces changes in Banf1's secondary structure, leading to the elimination of its DNA-binding capability. The study also demonstrated that phosphorylated Banf1 binds to DNA with lower affinity and less stable binding poses. These findings have implications for predicting the effects of Banf1 mutations on its DNA-binding capability and potential development of therapeutic drugs targeting cell proliferation.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2023)
Article
Multidisciplinary Sciences
Thais Sobanski, Amila Suraweera, Joshua T. Burgess, Iain Richard, Chee Man Cheong, Keyur Dave, Maddison Rose, Mark N. Adams, Kenneth J. O'Byrne, Derek J. Richard, Emma Bolderson
Summary: This study reveals that the glycolytic protein ALDOA plays a direct role in DNA double-strand break (DSB) repair. Upon DNA damage, ALDOA translocates into the nucleus and associates with the DNA DSB marker γ-H2AX. Depletion of ALDOA leads to increased DNA damage before and slower repair after ionising radiation. It is suggested that targeting ALDOA may be a potential strategy for simultaneous disruption of cancer metabolism and DNA repair.
SCIENTIFIC REPORTS
(2023)
