Review
Biochemistry & Molecular Biology
Chiara Frigerio, Elena Di Nisio, Michela Galli, Chiara Vittoria Colombo, Rodolfo Negri, Michela Clerici
Summary: DNA double-strand breaks (DSBs) are harmful DNA lesions that can lead to catastrophic consequences for genome stability. DSBs can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR), depending on the proteins that bind to the DSB ends and their regulation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Misaki Matsui, Shoki Kajita, Yuina Tsuchiya, Wakana Torii, Shiori Tamekuni, Ryotaro Nishi
Summary: Proper choice of DNA double-strand break (DSB) repair pathway is crucial for maintaining genome integrity. This study identifies USP49 as a novel enzyme that regulates ubiquitylation of DSB-induced gamma H2AX. Fine tuning of USP49 protein level and its deubiquitylation activity play important roles in cell sensitivity to DSB-inducing drug treatment.
Article
Biochemistry & Molecular Biology
Soichiro Kumamoto, Atsuya Nishiyama, Yoshie Chiba, Ryota Miyashita, Chieko Konishi, Yoshiaki Azuma, Makoto Nakanishi
Summary: Studies have shown the essential role of PARP1-HPF1 in LIG3-dependent Okazaki fragment joining, serving as a backup system for when LIG1 is nonfunctional. In the absence of LIG1, LIG3-XRCC1 can be recruited to chromatin for Okazaki fragment joining. Depletion of PARP1 or HPF1 leads to failure in recruiting LIG3 to chromatin, while co-depletion of LIG1 and XRCC1 completely prevents Okazaki fragment joining.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Multidisciplinary Sciences
Guangxue Liu, Jimin Li, Boxue He, Jiaqi Yan, Jingyu Zhao, Xuejie Wang, Xiaocong Zhao, Jingyan Xu, Yeyao Wu, Simin Zhang, Xiaoli Gan, Chun Zhou, Xiangpan Li, Xinghua Zhang, Xuefeng Chen
Summary: The yeast ubiquitin ligase Bre1 and its human homolog RNF20 function as recombination mediator proteins by promoting Rad51-ssDNA assembly and antagonizing the activities of Srs2 or FBH1 anti-recombinase. They interact with Rad51, direct Rad51 to ssDNA, and facilitate Rad51-ssDNA filament assembly and strand exchange. In addition, they counteract the disrupting effect of Srs2 or FBH1 helicase on the Rad51 filament. These findings reveal the important role of Bre1/RNF20 in homologous recombination repair.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Jong-Hyuk Lee, Raghavendra A. Shamanna, Tomasz Kulikowicz, Nima Borhan Fakouri, Edward W. Kim, Louise S. Christiansen, Deborah L. Croteau, Vilhelm A. Bohr
Summary: Werner syndrome (WS) is an accelerated aging disorder characterized by genomic instability caused by WRN protein deficiency. The phosphorylation of WRN by CDK2 on serine residue 426 is critical for WRN to choose between non-homologous end joining (NHEJ) and homologous recombination (HR) pathways. The phosphorylation stabilizes WRN's affinity for RPA and enhances its role in long-range resection, a crucial step for HR.
Review
Genetics & Heredity
Pierre Caron, Enrico Pobega, Sophie E. Polo
Summary: Recent studies have revealed the essential role of heterochromatin marks and associated factors in DNA double-strand break (DSB) repair pathways, influencing repair pathway choice within the nucleus. Heterochromatin features can affect DSB repair pathway choice and support repair processes within the cell nucleus.
FRONTIERS IN GENETICS
(2021)
Review
Genetics & Heredity
Shalini Aricthota, Paresh Priyadarshan Rana, Devyani Haldar
Summary: The packaging of the eukaryotic genome into chromatin presents a challenge for repairing DNA damage. DNA double-strand breaks (DSB) are the most harmful type of damage and require efficient repair. Recent research has shown that chromatin plays an active role in sensing, detecting, and repairing DNA damage. The repair of DSB involves the reorganization of chromatin, leading to changes in histone composition, nucleosome positioning, and histone modifications. Histone acetylation, in particular, plays a critical role in creating a favorable environment for DSB repair by opening up the chromatin structure and recruiting repair proteins.
FRONTIERS IN GENETICS
(2022)
Review
Biochemistry & Molecular Biology
Hirotomo Takatsuka, Atsushi Shibata, Masaaki Umeda
Summary: Plant DNA is vulnerable to environmental stressors, and chromatin plays a crucial role in protecting DNA by altering its structure. Changes in chromatin modifications, regulation of gene expression, and the physical barrier function of condensed chromatin are key mechanisms for plants to maintain genome integrity under genotoxic stress.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Vincent E. Provasek, Joy Mitra, Vikas H. Malojirao, Muralidhar L. Hegde
Summary: The continuous process of DNA damage and repair is crucial for maintaining genomic integrity. Among different types of DNA damage, double-strand breaks (DSBs) are the most dangerous and require timely repair. DSB repair is particularly important for nondividing, post-mitotic cells in the central nervous system (CNS), as failure in these mechanisms can lead to disruptions in neural networks and motor functions. In addition to repair pathways, DNA damage response (DDR) signaling and hnRNP proteins have been found to play important roles in neuronal DSB repair and are linked to age-associated neurological disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cell Biology
Huiming Lu, Anthony J. Davis
Summary: RecQ DNA helicases are a conserved protein family found in various organisms, playing important roles in cellular functions and potentially contributing to autosomal disorders.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ryo Sakasai, Tadashi Matsui, Yumi Sunatani, Kuniyoshi Iwabuchi
Summary: Camptothecin (CPT) shows cytotoxicity by inducing DNA double-strand breaks (DSBs) in DNA replication. The CPT-induced DSBs are considered to have only one DNA end, unlike radiation-induced DSBs that have two DNA ends. The cellular responses to one-ended and two-ended DSBs are not well understood.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Oncology
Xiaoqing Fan, Suling Sun, Haoran Yang, Huihui Ma, Chenggang Zhao, Wanxiang Niu, Junqi Fan, Zhiyou Fang, Xueran Chen
Summary: This study reveals the inactivation of the ZDHHC16/SETD2/H3K36me3 signaling axis in EGFR-altered GBM, which affects DNA damage repair signaling. The depalmitoylation inhibitor, PalmB, shows potential as a novel adjuvant treatment for GBM patients undergoing radiation therapy.
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
(2022)
Article
Biochemistry & Molecular Biology
Ioannis Emmanouilidis, Natalia Fili, Alexander W. Cook, Yukti Hari-Gupta, Alia dos Santos, Lin Wang, Marisa L. Martin-Fernandez, Peter J. I. Ellis, Christopher P. Toseland
Summary: Mammalian cells are constantly exposed to various DNA damaging events, leading to the activation of DNA repair pathways. Cas9-based genomic intervention allows for induced DSBs at defined quantities and locations across the human genome, utilizing custom-designed promiscuous guide RNAs based on in silico predictions. This provides a generic, low-cost, and rapid methodology for inducing controlled DNA damage in cell culture models.
Article
Oncology
Jiali Qin, Jie Fan, Gang Li, Shanting Liu, Zhensheng Liu, Yao Wu
Summary: The study found that radiation exposure may lead to mutations in DNA double-strand break repair genes, resulting in decreased DSB repair capacity and increased risk of PTMC.
CANCER CELL INTERNATIONAL
(2021)
Article
Biochemistry & Molecular Biology
Md Kawsar Mustofa, Yuki Tanoue, Mami Chirifu, Tatsuya Shimasaki, Chie Tateishi, Teruya Nakamura, Satoshi Tateishi
Summary: RAD18 plays a crucial role in DNA damage repair by promoting DNA damage-driven signaling and recruiting DNA repair proteins through ubiquitination.
JOURNAL OF BIOCHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Thomas Cremer, Marion Cremer, Barbara Huebner, Asli Silahtaroglu, Michael Hendzel, Christian Lanctot, Hilmar Strickfaden, Christoph Cremer
Article
Biochemistry & Molecular Biology
Hilmar Strickfaden, Thomas O. Tolsma, Ajit Sharma, D. Alan Underhill, Jeffrey C. Hansen, Michael J. Hendzel
Article
Biochemistry & Molecular Biology
Andrew J. Locke, Lazina Hossain, Glynnis McCrostie, Daryl A. Ronato, Amira Fitieh, Tanzeem Ahmed Rafique, Fatemeh Mashayekhi, Mobina Motamedi, Jean-Yves Masson, Ismail Hassan Ismail
Summary: In this study, it was found that CtIP recruitment to sites of DNA damage and replication stress is impaired upon global inhibition of SUMOylation. It was demonstrated that CUP is a target for modification by SUMO-2 and that this occurs constitutively during S phase. The results shed further light on the coordinated regulation of CtIP by SUMOylation in the maintenance of genome stability.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Multidisciplinary Sciences
Haithem Barbour, Salima Daou, Michael Hendzel, El Bachir Affar
NATURE COMMUNICATIONS
(2020)
Editorial Material
Biotechnology & Applied Microbiology
Tasnim H. Beacon, James R. Davie, Michael J. Hendzel
Review
Biochemistry & Molecular Biology
Amira Fitieh, Andrew J. Locke, Mobina Motamedi, Ismail Hassan Ismail
Summary: Polycomb group proteins play roles in stem cell maintenance, gene silencing, and DNA damage repair. BMI1, a member of PRC1, is involved in DNA repair and genome integrity, making it a potential pharmacological target.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Mohammad A. M. Ali, Javier A. Garcia-Vilas, Christopher R. Cromwell, Basil P. Hubbard, Michael J. Hendzel, Richard Schulz
Summary: Matrix metalloproteinase-2 is found in the nucleolus where it regulates ribosomal RNA transcription, facilitating cell proliferation. By cleaving the N-terminal tail of histone H3, it enhances the transcription of ribosomal RNA, impacting cell proliferation.
Review
Genetics & Heredity
Jeffrey C. Hansen, Kazuhiro Maeshima, Michael J. Hendzel
Summary: The review delves into the principles of phase separation, the history of chromatin aggregation studies, the process of liquid-solid phase separation of chromatin driven by self-interaction, and the occurrence of liquid-liquid phase separation of chromatin under specific solution conditions. It discusses the LLPS phenomena of chromatin-associated proteins, highlighting the importance of chromatin self-interaction in genome structure.
EPIGENETICS & CHROMATIN
(2021)
Review
Biochemistry & Molecular Biology
Jana Yasser Hafez Ali, Amira Mohammed Fitieh, Ismail Hassan Ismail
Summary: This review discusses how the dysregulation of DNA repair pathways in multiple myeloma exacerbates genomic instability and chromosomal abnormalities, leading to disease progression and drug resistance.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Amira Fitieh, Andrew J. Locke, Fatemeh Mashayekhi, Fajr Khaliqdina, Ajit K. Sharma, Ismail Hassan Ismail
Summary: BMI-1 is a crucial regulator of gene transcriptional silencing during development. Its role in the DNA damage response has recently gained attention, but the exact mechanism remains unclear. This study establishes that BMI-1 plays an important role in the repair of DNA double-strand breaks through homologous recombination by promoting DNA end resection. Mechanistically, BMI-1 facilitates the recruitment of CtIP, allowing accumulation of RPA and RAD51 at DNA damage sites. Additionally, H2A ubiquitylation at K119 has been found to promote end resection.
Article
Biochemistry & Molecular Biology
Faisal Bin Rashed, Diana Diaz-Dussan, Fatemeh Mashayekhi, Dawn Macdonald, Patrick Nicholas Nation, Xiao-Hong Yang, Sargun Sokhi, Alexandru Cezar Stoica, Hassan El-Saidi, Carolynne Ricardo, Ravin Narain, Ismail Hassan Ismail, Leonard Irving Wiebe, Piyush Kumar, Michael Weinfeld
Summary: Solid tumors often exhibit resistance to standard treatment due to poor oxygenation. Nitroimidazoles (NIs) can selectively target hypoxic cells and show potential as hypoxia-directed therapeutics. In a head and neck cancer model, hypoxic cells were found to be more sensitive to IAZA and FAZA, which altered cell morphology, compromised DNA replication, slowed down cell cycle progression, induced replication stress, and ultimately led to cytostasis.
Article
Biochemical Research Methods
Ajit K. Sharma, Amira Mohammed Fitieh, Andrew J. Locke, Jana Yasser Hafez Ali, Ismail Hassan Ismail
Summary: Here, we present a chromatin immunoprecipitation-based protocol for quantifying the recruitment of proteins adjacent to site-specific DNA double-strand breaks. This method involves inducing DSBs in U2OS osteosarcoma cells expressing specific restriction endonucleases and performing chromatin isolation, immunoprecipitation, protein elution, and quantitative PCR-based DNA quantification.
Article
Biochemistry & Molecular Biology
Julia O'Sullivan, Charu Kothari, Marie-Christine Caron, Jean-Philippe Gagne, Zhigang Jin, Louis Nonfoux, Adele Beneyton, Yan Coulombe, Melissa Thomas, Nurgul Atalay, X. Wei Meng, Larissa Milano, Dominique Jean, Francois-Michel Boisvert, Scott H. Kaufmann, Michael J. Hendzel, Jean-Yves Masson, Guy G. Poirier
Summary: Zinc finger (ZNF) motifs are frequently occurring domains in the human genome and have recently been found to regulate genome integrity. This study identifies a novel PAR reader protein called ZNF432, which plays a key role in balancing the outcome of PARPi response by regulating homologous recombination.
NUCLEIC ACIDS RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Adele Beneyton, Louis Nonfoux, Jean-Philippe Gagne, Amelie Rodrigue, Charu Kothari, Nurgul Atalay, Michael J. Hendzel, Guy G. Poirier, Jean-Yves Masson
Summary: Poly(ADP-ribosylation) (PARylation) is a highly regulated process that involves the addition of polymers of ADP-ribose (PAR) to substrate proteins or interactions with PAR. It plays a crucial role in maintaining genomic stability and has gained attention for its involvement in synthetic lethality, especially in HR-deficient breast and ovarian tumors. Understanding PAR-dependent mechanisms is important due to the challenge of PARPi resistance in the clinic.
Article
Biochemical Research Methods
Ajit K. Sharma, Amira Mohammed Fitieh, Jana Yasser Hafez Ali, Ismail Hassan Ismail
Summary: DNA end resection is a critical step in repairing DNA double-strand breaks (DSBs) through homologous recombination. This article describes a quantitative polymerase-chain-reaction-based method to measure the formation of single-stranded DNA (ssDNA) intermediates during DNA end resection. The ER-AsiSI system is used to digest unresected double-stranded DNA at DSB sites using restriction endonucleases with differential digestion patterns.
