scholarly journals ZATT (ZNF451)–mediated resolution of topoisomerase 2 DNA-protein cross-links

Science ◽  
2017 ◽  
Vol 357 (6358) ◽  
pp. 1412-1416 ◽  
Author(s):  
Matthew J. Schellenberg ◽  
Jenna Ariel Lieberman ◽  
Andrés Herrero-Ruiz ◽  
Logan R. Butler ◽  
Jason G. Williams ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cellular Responses ◽  
Hydrolase Activity ◽  
Reaction Intermediate ◽  
Sumo Ligase ◽  
Topoisomerase 2 ◽  
Cross Links ◽  
Repair Factor ◽  
Cleavage Complex

Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a “split-SIM” SUMO2 engagement platform. These findings uncover a ZATT-TDP2–catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.

scholarly journals Two Sides of the Same Coin: TFIIH Complexes in Transcription and DNA Repair

2010 ◽  
Vol 10 ◽  
pp. 633-643 ◽  
Author(s):  
Alexander Zhovmer ◽  
Valentyn Oksenych ◽  
Frédéric Coin
Keyword(s):  
Dna Repair ◽  
Western Blotting ◽  
Chromatin Immunoprecipitation ◽  
Transcription Initiation ◽  
Dna Lesions ◽  
Dynamic Composition ◽  
The Core ◽  
Repair Factor ◽  
A New Technique ◽  
Two Sides

TFIIH is organized into a seven-subunit core associated with a three-subunit Cdk-activating kinase (CAK) module. TFIIH has roles in both transcription initiation and DNA repair. During the last 15 years, several studies have been conducted to identify the composition of the TFIIH complex involved in DNA repair. Recently, a new technique combining chromatin immunoprecipitation and western blotting resolved the hidden nature of the TFIIH complex participating in DNA repair. Following the recruitment of TFIIH to the damaged site, the CAK module is released from the core TFIIH, and the core subsequently associates with DNA repair factors. The release of the CAK is specifically driven by the recruitment of the DNA repair factor XPA and is required to promote the incision/excision of the damaged DNA. Once the DNA lesions have been repaired, the CAK module returns to the core TFIIH on the chromatin, together with the release of the repair factors. These data highlight the dynamic composition of a fundamental cellular factor that adapts its subunit composition to the cell needs.

scholarly journals The Pso4 mRNA Splicing and DNA Repair Complex Interacts with WRN for Processing of DNA Interstrand Cross-links

2005 ◽  
Vol 280 (49) ◽  
pp. 40559-40567 ◽  
Author(s):  
Nianxiang Zhang ◽  
Ramandeep Kaur ◽  
Xiaoyan Lu ◽  
Xi Shen ◽  
Lei Li ◽  
...  
Keyword(s):  
Dna Repair ◽  
Mrna Splicing ◽  
Interstrand Cross Links ◽  
Cross Links

Study of UV-induced DNA Repair Factor Recruitment: Kinetics and Dynamics

2017 ◽  
pp. 101-105 ◽  
Author(s):  
Sarah Sertic ◽  
Stefania Roma ◽  
Paolo Plevani ◽  
Federico Lazzaro ◽  
Marco Muzi-Falconi
Keyword(s):  
Dna Repair ◽  
Kinetics And Dynamics ◽  
Repair Factor

scholarly journals Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2684 ◽  
Author(s):  
Giacomo Milletti ◽  
Luisa Strocchio ◽  
Daria Pagliara ◽  
Katia Girardi ◽  
Roberto Carta ◽  
...  
Keyword(s):  
Dna Repair ◽  
Fanconi Anemia ◽  
Clinical Phenotype ◽  
Bone Marrow Failure ◽  
Therapeutic Approaches ◽  
Dna Repair Mechanisms ◽  
Solid Malignancies ◽  
Interstrand Cross Links ◽  
Repair Mechanisms ◽  
Cross Links

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches.

scholarly journals WHO HAS THERAPY-RELATED AML?

2017 ◽  
Vol 9 (1) ◽  
pp. e2017025 ◽  
Author(s):  
Robert Gale ◽  
John M. Bennett ◽  
F. Owen Hoffman
Keyword(s):  
Dna Repair ◽  
Cancer Therapy ◽  
Gene Variants ◽  
Topoisomerase Inhibitors ◽  
Dna Intercalators ◽  
Myeloid Neoplasm ◽  
Anti Cancer ◽  
Topoisomerase 2 ◽  
Or Gene ◽  
Ionizing Radiations

Therapy-related leukemia or therapy-related myeloid neoplasm are widely-used terms to designate leukemia developing in persons who previously received anti-cancer therapy (for example, see references 1, 2), especially if the prior anti-cancer therapy included drugs such as alkylators, DNA-intercalators, topoisomerase-2-inhibitors, purines and/or ionizing radiations.   Sometimes specific genes such as AML1, EVI1, NRAS or MLL are mutated by therapy or gene variants are produced which activate mutagens or interfere with DNA repair, such FANC, NQ01 or AML2. 3-5   But how can we know if AML in someone is a therapy-related?Keywords: Therapy-related leukemia; alkylators; ionizing radiations; Topoisomerase Inhibitors; DNA Repair

scholarly journals DNA-Histone Cross-Links: Formation and Repair

2020 ◽  
Vol 8 ◽  
Author(s):  
Manideep C. Pachva ◽  
Alexei F. Kisselev ◽  
Bakhyt T. Matkarimov ◽  
Murat Saparbaev ◽  
Regina Groisman
Keyword(s):  
Dna Repair ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
Genotoxic Stress ◽  
Tumor Resistance ◽  
Cross Link ◽  
Covalent Bonds ◽  
Nucleosome Core ◽  
Cross Links ◽  
Tight Association

The nucleosome is a stretch of DNA wrapped around a histone octamer. Electrostatic interactions and hydrogen bonds between histones and DNA are vital for the stable organization of nucleosome core particles, and for the folding of chromatin into more compact structures, which regulate gene expression via controlled access to DNA. As a drawback of tight association, under genotoxic stress, DNA can accidentally cross-link to histone in a covalent manner, generating a highly toxic DNA-histone cross-link (DHC). DHC is a bulky lesion that can impede DNA transcription, replication, and repair, often with lethal consequences. The chemotherapeutic agent cisplatin, as well as ionizing and ultraviolet irradiations and endogenously occurring reactive aldehydes, generate DHCs by forming either stable or transient covalent bonds between DNA and side-chain amino groups of histone lysine residues. The mechanisms of DHC repair start to unravel, and certain common principles of DNA-protein cross-link (DPC) repair mechanisms that participate in the removal of cross-linked histones from DNA have been described. In general, DPC is removed via a two-step repair mechanism. First, cross-linked proteins are degraded by specific DPC proteases or by the proteasome, relieving steric hindrance. Second, the remaining DNA-peptide cross-links are eliminated in various DNA repair pathways. Delineating the molecular mechanisms of DHC repair would help target specific DNA repair proteins for therapeutic intervention to combat tumor resistance to chemotherapy and radiotherapy.

scholarly journals Erratum: Ubiquitous overexpression of the DNA repair factor dPrp19 reduces DNA damage and extends Drosophila life span

2017 ◽  
Vol 3 (1) ◽  
Author(s):  
Kathrin Garschall ◽  
Hanna Dellago ◽  
Martina Gáliková ◽  
Markus Schosserer ◽  
Thomas Flatt ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Life Span ◽  
Repair Factor

T2 Phage Sensitization by Linear and Angular Furocoumarins

1979 ◽  
Vol 34 (9-10) ◽  
pp. 811-814 ◽  
Author(s):  
F. Baccichetti ◽  
F. Bordin ◽  
F. Carlassare ◽  
A. Guiotto
Keyword(s):  
Dna Repair ◽  
Survival Curves ◽  
Killing Activity ◽  
Virus Core ◽  
Cross Links

Abstract T2 bacteriophage sensitization has been studied using two furocoumarins capable of linking co­valently to DNA to the same extent but producing different damages, psoralen and 4,5′-dimethylangelicin. Psoralen is a well-known linear furocoumarin capable of inducing in DNA both mono-adducts and cross-links; 4,5′-dimethylangelicin is a new angular compound known as a pure mo­nofunctional reagent. In the sensitization of T2 mature virions both drugs proved very active, yielding survival curves practically superimposable; on the contrary, in the experiments with the T2 veg­etative form, i. e. its DNA inside the host, 4,5′-dimethylangelicin resulted much less effective, resembling the picture observed in the inactivation of the host bacteria. This result did not appear related to an enhancement of DNA repair by a Weigle effect. The different killing activity of 4,5′-dimethylangelicin can be explained supposing that this drug is capable of inducing cross-links in T2 DNA inside the virus core, in which it exists in a very folded form, but not in the same DNA after injection into the host bacteria.

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