Article
Multidisciplinary Sciences
Nicholas A. W. Bell, Philip J. Haynes, Katharina Brunner, Taiana Maia de Oliveira, Maria M. Flocco, Bart W. Hoogenboom, Justin E. Molloy
Summary: PARP1 binds and condenses undamaged DNA by stabilizing DNA loops, and blocks condensation reversal for damaged DNA in the presence of NAD(+), suggesting a mechanism for PARP1 in the organization of chromatin structure.
Article
Biochemistry & Molecular Biology
Li-Kuang Tsai, Min Peng, Chia-Chun Chang, Luan Wen, Lin Liu, Xiubin Liang, Y. Eugene Chen, Jie Xu, Li-Ying Sung
Summary: This study reveals that ZSCAN4 promotes DNA repair in mESCs by interacting with PARP1 and reducing DSB. PARP1 binds directly to ZSCAN4, with the second α-helix and the fourth zinc finger motif of ZSCAN4 playing a critical role in this interaction.
CELL AND BIOSCIENCE
(2023)
Article
Biology
Erwan Goy, Maxime Tomezak, Caterina Facchin, Nathalie Martin, Emmanuel Bouchaert, Jerome Benoit, Clementine de Schutter, Joe Nassour, Laure Saas, Claire Drullion, Priscille M. Brodin, Alexandre Vandeputte, Olivier Molendi-Coste, Laurent Pineau, Gautier Goormachtigh, Olivier Pluquet, Albin Pourtier, Fabrizio Cleri, Eric Lartigau, Nicolas Penel, Corinne Abbadie
Summary: Induction of second primary cancers is a rare but severe complication of curative-intent radiation therapy. Research shows that normal human or mouse dermal fibroblasts exposed to out-of-field radiation dose at the margin of the target volume do not die, but enter a long-lived senescent state, leading to the accumulation of unrepaired DNA single-strand breaks. Some of these senescent cells eventually escape cell cycle arrest and give rise to daughter cells with mutations and invasive properties. This discovery highlights the role of single-strand break-induced senescence as the mechanism of second primary cancer initiation, with potential implications for prevention.
Article
Biochemistry & Molecular Biology
Zhong-Xuan Wang, Yi Liu, Yao-Lin Li, Qiao Wei, Rong-Rong Lin, Ruiqing Kang, Yang Ruan, Zhi-Hao Lin, Nai-Jia Xue, Bao-Rong Zhang, Jia-Li Pu
Summary: DNA damage and defective DNA repair are implicated in neurodegeneration of Parkinson's disease. The study shows that the protein DJ-1 plays a crucial role in modulating DNA double-strand break repair by promoting both homologous recombination and nonhomologous end joining. DJ-1 interacts with PARP1 and enhances its enzymatic activity during DNA repair. Importantly, PD patients with DJ-1 mutation have impaired PARP1 activity and DSB repair.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Dong Wang, Bethany Veo, Angela Pierce, Susan Fosmire, Krishna Madhavan, Ilango Balakrishnan, Andrew Donson, Irina Alimova, Kelly D. Sullivan, Molishree Joshi, Mark Erlander, Maya Ridinger, Nicholas K. Foreman, Sujatha Venkataraman, Rajeev Vibhakar
Summary: PLK1 is overexpressed in Group 3 MB, and Onvansertib shows efficacy in reducing colony formation, cell proliferation, inducing G2/M arrest, and enhancing DNA damage and apoptosis in combination with radiation therapy in vitro and in xenografts, suggesting its potential as an effective strategy for MB treatment.
Article
Multidisciplinary Sciences
Jianfeng Shu, Xiaofang Wang, Xuejie Yang, Guofang Zhao
Summary: TOP2 poisons are widely used chemotherapeutics for systemic cancers, but they have unwanted side effects and drug resistance. In this study, we found that combining an ATM inhibitor with TOP2 poison can enhance therapeutic efficiency and reduce side effects, potentially lowering cardiotoxicity and secondary malignancy associated with therapy.
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Kai Wang, Yizhou Wu, Lizhu Lai, Xin Wang, Shuya Sun
Summary: This study reveals the conformational changes in PAPR1 and the differences in key residue interactions induced by inhibitors through comparative molecular dynamics simulations and energy decomposition. It shows that inhibitors indirectly affect some residues in the CAT domain that interact with DNA and other domains. Additionally, the binding energy of CAT/ligand may not accurately measure the ligand activity compared to PARP1/DNA/ligand.
Article
Biology
Luis Gregory Zamalloa, Margaret M. Pruitt, Nicole M. Hermance, Himabindu Gali, Rachel L. Flynn, Amity L. Manning
Summary: This study investigates the impact of RB dysfunction on genome stability and whether this change can be exploited in RB-deficient cancer cells. The findings demonstrate that RB loss leads to high levels of PARylation, and inhibiting PARylation allows RB-deficient cells to progress to mitosis despite replication stress. These defects result in high levels of DNA damage and compromised cell viability. Therefore, drugs targeting PARP1 and PARP2 may have clinical relevance in the treatment of RB-deficient cancers.
LIFE SCIENCE ALLIANCE
(2023)
Article
Oncology
Yang Liang, Yuefeng Qin, Guoyun Jiang, Wenli Feng, Ying Yuan
Summary: This study reveals the potential role of MDC1 in the treatment of CML and suggests it as an alternative option for IM drug resistance dilemma, by regulating the DNA damage repair mechanism.
Article
Oncology
Xu Zhao, Yuan Ma, Jing Li, Xuanzi Sun, Yuchen Sun, Fengyi Qu, Xiaobo Shi, Yuchen Xie, Siqi Liu, Yanfang Ma, Chao Ji, Weibin Hu, Shaomin Che, Xiaozhi Zhang
Summary: The overexpression of AEG-1 in esophageal squamous cell carcinoma (ESCC) plays a crucial role in radioresistance by recruiting the deubiquitinase USP10 to promote DNA damage repair, leading to increased radioresistance. These findings provide potential therapeutic targets to enhance the efficacy of radiotherapy in ESCC.
Article
Multidisciplinary Sciences
Ethan S. Lavi, Z. Ping Lin, Elena S. Ratner
Summary: This study investigated the effects of non-homologous end-joining (NHEJ) genes on clinical outcomes of ovarian cancer patients, and identified several most important genes for predicting the prognosis of ovarian cancer patients.
Review
Cell Biology
Rodrigo E. Caceres-Gutierrez, Yair Alfaro-Mora, Marco A. Andonegui, Jose Diaz-Chavez, Luis A. Herrera
Summary: RAS oncogenes are major drivers of tumorigenesis, and their mutation predicts poor outcomes and treatment resistance. Targeting RAS mutants has been a challenge, and indirect approaches face complex feedback mechanisms. Mutant RAS increases cellular stress, but adaptive responses alleviate these conditions, allowing cancer cells to survive and resist treatment. However, these cellular mechanisms become crucial to cancer cells and can be exploited as vulnerabilities.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Michael Schmalz, Xiao- Xuan Liang, Ines Wieser, Caroline Gruschel, Lukas Muskalla, Martin Thomas Stoeckl, Roland Nitschke, Norbert Linz, Alfred Leitenstorfer, Alfred Vogel, Elisa Ferrando-May, Wei Yang
Summary: Understanding and predicting the outcome of light-DNA interaction is crucial for DNA repair and radiotherapy. This study combines laser microirradiation, imaging, and modeling to investigate the damage pathways in live cells. The results show that photochemical damage dominates at 515 nm, while electron-mediated damage dominates at wavelengths ≥620 nm. The study provides a conceptual framework for interpreting the wavelength-dependent DNA damage induced by laser and electron interactions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Johannes Rudolph, Uma M. Muthurajan, Megan Palacio, Jyothi Mahadevan, Genevieve Roberts, Annette H. Erbse, Pamela N. Dyer, Karolin Luger
Summary: PARP1 is a key player in DNA damage response and a target for cancer treatment. The BRCT domain binds to DNA without activating the catalytic domain. The DNA-binding properties of the BRCT domain contribute to the monkey-bar mechanism for DNA transfer of PARP1.
Article
Cell Biology
Qian Chen, Kai Ma, Xiuhua Liu, Shih-Hsun Chen, Peng Li, Yonghao Yu, Anthony K. L. Leung, Xiaochun Yu
Summary: In this study, truncated PARP1 (tPARP1) was found to interact with the RNA polymerase III (Pol III) complex in the cytosol during apoptosis. tPARP1 was shown to facilitate the mono-ADP-ribosylation of RNA Pol III and contribute to IFN-beta production and apoptosis. Inhibiting PARP1 or expressing the non-cleavable form of PARP1 resulted in impairment of these molecular events.
Article
Multidisciplinary Sciences
Emil Mladenov, Xiaoxiang Fan, Rositsa Dueva, Aashish Soni, George Iliakis
SCIENTIFIC REPORTS
(2019)
Article
Multidisciplinary Sciences
Emil Mladenov, Xiaoxiang Fan, Katja Paul-Konietzko, Aashish Soni, George Iliakis
SCIENTIFIC REPORTS
(2019)
Article
Biochemistry & Molecular Biology
Emil Mladenov, Christian Staudt, Aashish Soni, Tamara Murmann-Konda, Maria Siemann-Loekes, George Iliakis
NUCLEIC ACIDS RESEARCH
(2020)
Article
Genetics & Heredity
Aashish Soni, Tamara Murmann-Konda, Maria Siemann-Loekes, Gabriel E. Pantelias, George Iliakis
Article
Genetics & Heredity
Aashish Soni, Emil Mladenov, George Iliakis
Summary: The repair pathways of DNA double strand breaks (DSBs) collaborate with DNA damage cell cycle checkpoints to protect genomic stability in cells exposed to ionizing radiation. Checkpoints are known to facilitate the function of DSB repair pathways, but the feedback of DSB repair proficiency into checkpoint activation has been less investigated. In cells deficient in homologous recombination repair (HRR), the activation of the G(2)-checkpoint is severely impaired after exposure to low IR doses in the G(2)-phase. This shows the close intertwining of HRR and the ATM/ATR-dependent G(2)-checkpoint in cells exposed to low IR-doses in G(2)-phase, indicating that HRR dominates in this context.
Article
Biotechnology & Applied Microbiology
Tamara Murmann-Konda, Aashish Soni, Martin Stuschke, George Iliakis
Summary: The study demonstrates that low doses of ionizing radiation primarily repair DSBs through HR, while high doses mainly utilize c-NHEJ. In G(2)-phase cells, DSBs causing chromatid breaks are also repaired in a similar fashion. Furthermore, a pathway switch from HR to c-NHEJ occurs with increasing radiation dose in the processing of these specific DSBs.
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
(2021)
Article
Public, Environmental & Occupational Health
Aggeliki Nikolakopoulou, Aashish Soni, Martha Habibi, Pantelis Karaiskos, Gabriel Pantelias, Georgia Terzoudi, George Iliakis
Summary: Although technological advances in radiation oncology have improved the delivery of radiation dose and reduced side effects, there is still a need to better understand the mechanisms underlying DNA damage response (DDR) and overcome tumor resistance. Effective signaling pathways enable cell cycle arrest for DNA repair, and key kinases like ATM, ATR, and Chk1 play a crucial role in this process. Establishing a cytogenetic assay to evaluate the potency of DDR inhibitors for radiosensitization is important for assessing treatment efficacy.
FRONTIERS IN PUBLIC HEALTH
(2021)
Article
Biochemistry & Molecular Biology
Lisa Marie Krieger, Emil Mladenov, Aashish Soni, Marilen Demond, Martin Stuschke, George Iliakis
Summary: The decompaction of chromatin induced by hypotonic stress affects the processing and repair of DNA double-strand breaks (DSBs), leading to increased sensitivity of cells to ionizing radiation-induced damage and compromising genomic stability. This is achieved through suppression of homologous recombination (HR) and enhancement of error-prone processing by alternative end-joining (alt-EJ) and single-strand annealing (SSA).
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Christina Hassiepen, Aashish Soni, Ines Rudolf, Vivian Boron, Sebastian Oeck, George Iliakis, Alexander Schramm
Summary: Neuroblastoma with high expression of TrkA/NTRK1 is associated with better prognosis, but the impact of TrkA/NTRK1 on radiation response is not well understood. This study found that TrkA/NTRK1-expressing cells fail to activate the G2/M cell cycle checkpoint after irradiation, leading to increased short-term cell viability. The deficient G2/M-checkpoint upon DNA damage induced by ionizing radiation in TrkA/NTRK1-activated cells suggests a potential role of NTRK signaling in checkpoint regulation and response to radiation.
Article
Biochemistry & Molecular Biology
Aashish Soni, Xiaolu Duan, Martin Stuschke, George Iliakis
Summary: The activation of the intra-S-phase checkpoint is essential for maintaining genomic stability and involves the activities of ATM and ATR. DNA-PKcs also contributes to the recovery from the checkpoint. The organization of the intra-S-phase checkpoint is similar to that of the G(2) checkpoint.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Huaping Xiao, Fanghua Li, Emil Mladenov, Aashish Soni, Veronika Mladenova, Bing Pan, Rositsa Dueva, Martin Stuschke, Beate Timmermann, George Iliakis
Summary: The load of DNA double-strand breaks induced by ionizing radiation plays a key role in determining the repair pathway choice in higher eukaryotes. The integration of DNA-PKcs into resection regulation suggests a mechanism adaptively facilitating resection. Mutations in DNA-PKcs result in hyper-resection, ruling out the competition between c-NHEJ and HR as the cause of increased resection.
Article
Biochemistry & Molecular Biology
Xile Pei, Emil Mladenov, Aashish Soni, Fanghua Li, Martin Stuschke, George Iliakis
Summary: The study investigates the role of PTEN in DNA double-strand break (DSB) repair. The loss of PTEN sensitizes cells to radiation by suppressing RAD51 expression and inhibiting homologous recombination, leading to an increase in error-prone single strand annealing.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Oncology
Aashish Soni, Xixi Lin, Emil Mladenov, Veronika Mladenova, Martin Stuschke, George Iliakis
Summary: PARP inhibitors have broad applicability in treating tumors with HR defects, but their combination with radiotherapy is less advanced. Talazoparib is a superior radiosensitizer compared to other PARP inhibitors and has the potential to treat various forms of cancer. The strong radiosensitizing potential of Talazoparib may be due to its unique mechanisms in DNA double-strand break repair pathways.
Article
Cell Biology
Fanghua Li, Emil Mladenov, Yanjie Sun, Aashish Soni, Martin Stuschke, Beate Timmermann, George Iliakis
Summary: Alt-EJ is an error-prone DNA double-strand break repair pathway that is active when primary repair pathways, c-NHEJ and HR, are defective or fail. It depends on DNA end-resection, initiated by the CtIP/MRE11-RAD50-NBS1 complex and extended by EXO1 or BLM/DNA2 complex. Alt-EJ is regulated by the cell cycle phase, with maximum activity in G(2)-phase and reduced activity in G(1)-phase and quiescent G(0)-phase cells. CtIP-dependent resection is identified as the key regulator of Alt-EJ in G(1)- and G(0)-phase cells, with low levels of CtIP allowing modest resection and Alt-EJ in G(1)-phase cells and undetectable CtIP and Alt-EJ in G(0)-phase cells.
Article
Cell Biology
Daxian Luo, Emil Mladenov, Aashish Soni, Martin Stuschke, George Iliakis
Summary: We have previously reported that ATM and ATR regulate the G(2)-checkpoint in G(2)-phase cells sustaining low loads of DNA double-strand break (DSBs), with ATR at the output-node through Chk1. However, the partial response generated by inhibition of Chk1 suggested involvement of additional kinases downstream of ATR. In this study, we found that specific Chk1 inhibitors have weaker effects on G(2)-checkpoint compared to ATR inhibitors, and identified p38a and MK2 as backup checkpoint effectors. These findings expand the understanding of signaling pathways involved in G(2)-checkpoint activation and provide potential targets for enhancing radiosensitivity in tumor cells.
