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ICL repair

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https://www.readbyqxmd.com/read/29137116/altering-residue-134-confers-an-increased-substrate-range-of-alkylated-nucleosides-to-the-e-coli-ogt-protein
#1
Nadia M Schoonhoven, Derek K O'Flaherty, Francis P McManus, Lauralicia Sacre, Anne M Noronha, M Judith Kornblatt, Christopher J Wilds
O⁶-Alkylguanine-DNA alkyltransferases (AGTs) are proteins responsible for the removal of mutagenic alkyl adducts at the O⁶-atom of guanine and O⁴-atom of thymine. In the current study we set out to understand the role of the Ser134 residue in the Escherichia coli AGT variant OGT on substrate discrimination. The S134P mutation in OGT increased the ability of the protein to repair both O⁶-adducts of guanine and O⁴-adducts of thymine. However, the S134P variant was unable, like wild-type OGT, to repair an interstrand cross-link (ICL) bridging two O⁶-atoms of guanine in a DNA duplex...
November 11, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29091773/sensing-and-processing-of-dna-interstrand-crosslinks-by-the-mismatch-repair-pathway
#2
Niyo Kato, Yoshitaka Kawasoe, Hannah Williams, Elena Coates, Upasana Roy, Yuqian Shi, Lorena S Beese, Orlando D Schärer, Hong Yan, Max E Gottesman, Tatsuro S Takahashi, Jean Gautier
DNA interstrand crosslinks (ICLs) that are repaired in non-dividing cells must be recognized independently of replication-associated DNA unwinding. Using cell-free extracts from Xenopus eggs that support neither replication nor transcription, we establish that ICLs are recognized and processed by the mismatch repair (MMR) machinery. We find that ICL repair requires MutSα (MSH2-MSH6) and the mismatch recognition FXE motif in MSH6, strongly suggesting that MutSα functions as an ICL sensor. MutSα recruits MutLα and EXO1 to ICL lesions, and the catalytic activity of both these nucleases is essential for ICL repair...
October 31, 2017: Cell Reports
https://www.readbyqxmd.com/read/29059323/fanci-and-fancd2-have-common-as-well-as-independent-functions-during-the-cellular-replication-stress-response
#3
Elizabeth L Thompson, Jung E Yeo, Eun-A Lee, Yinan Kan, Maya Raghunandan, Constanze Wiek, Helmut Hanenberg, Orlando D Schärer, Eric A Hendrickson, Alexandra Sobeck
Fanconi anemia (FA) is an inherited cancer predisposition syndrome characterized by cellular hypersensitivity to DNA interstrand crosslinks (ICLs). To repair these lesions, the FA proteins act in a linear hierarchy: following ICL detection on chromatin, the FA core complex monoubiquitinates and recruits the central FANCI and FANCD2 proteins that subsequently coordinate ICL removal and repair of the ensuing DNA double-stranded break by homology-dependent repair (HDR). FANCD2 also functions during the replication stress response by mediating the restart of temporarily stalled replication forks thereby suppressing the firing of new replication origins...
November 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29051491/fan1-interaction-with-ubiquitylated-pcna-alleviates-replication-stress-and-preserves-genomic-integrity-independently-of-brca2
#4
Antonio Porro, Matteo Berti, Julia Pizzolato, Serena Bologna, Svenja Kaden, Anja Saxer, Yue Ma, Kazuo Nagasawa, Alessandro A Sartori, Josef Jiricny
Interstrand cross-link (ICL) hypersensitivity is a characteristic trait of Fanconi anemia (FA). Although FANCD2-associated nuclease 1 (FAN1) contributes to ICL repair, FAN1 mutations predispose to karyomegalic interstitial nephritis (KIN) and cancer rather than to FA. Thus, the biological role of FAN1 remains unclear. Because fork stalling in FAN1-deficient cells causes chromosomal instability, we reasoned that the key function of FAN1 might lie in the processing of halted replication forks. Here, we show that FAN1 contains a previously-uncharacterized PCNA interacting peptide (PIP) motif that, together with its ubiquitin-binding zinc finger (UBZ) domain, helps recruit FAN1 to ubiquitylated PCNA accumulated at stalled forks...
October 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/29031493/beyond-interstrand-crosslinks-repair-contribution-of-fancd2-and-other-fanconi-anemia-proteins-to-the-replication-of-dna
#5
REVIEW
Maria B Federico, Paola Campodónico, Natalia S Paviolo, Vanesa Gottifredi
Biallelic mutations of FANCD2 and other components of the Fanconi Anemia (FA) pathway cause a disease characterized by bone marrow failure, cancer predisposition and a striking sensitivity to agents that induce crosslinks between the two complementary DNA strands (inter-strand crosslinks-ICL). Such genotoxins were used to characterize the contribution of the FA pathway to the genomic stability of cells, thus unravelling the biological relevance of ICL repair in the context of the disease. Notwithstanding this, whether the defect in ICL repair as the sole trigger for the multiple physiological alterations observed in FA patients is still under investigation...
September 14, 2017: Mutation Research
https://www.readbyqxmd.com/read/29020621/fanconi-anemia-associated-mutations-destabilize-rad51-filaments-and-impair-replication-fork-protection
#6
Karina Zadorozhny, Vincenzo Sannino, Ondrej Beláň, Jarmila Mlčoušková, Mário Špírek, Vincenzo Costanzo, Lumír Krejčí
Fanconi anemia (FA) is a genetic disorder characterized by a defect in DNA interstrand crosslink (ICL) repair, chromosomal instability, and a predisposition to cancer. Recently, two RAD51 mutations were reported to cause an FA-like phenotype. Despite the tight association of FA/HR proteins with replication fork (RF) stabilization during normal replication, it remains unknown how FA-associated RAD51 mutations affect replication beyond ICL lesions. Here, we report that these mutations fail to protect nascent DNA from MRE11-mediated degradation during RF stalling in Xenopus laevis egg extracts...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/29017571/dna-damage-response-and-cancer-therapeutics-through-the-lens-of-the-fanconi-anemia-dna-repair-pathway
#7
REVIEW
Sonali Bhattacharjee, Saikat Nandi
Fanconi Anemia (FA) is a rare, inherited genomic instability disorder, caused by mutations in genes involved in the repair of interstrand DNA crosslinks (ICLs). The FA signaling network contains a unique nuclear protein complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. FA proteins act at different steps of ICL repair in sensing, recognition and processing of DNA lesions...
October 10, 2017: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/28966006/accidental-duplication-beyond-interstrand-crosslinks-repair-contribution-of-fancd2-and-other-fanconi-anemia-proteins-to-the-replication-of-dna
#8
Maria B Federico, Paola Campodónico, Natalia S Paviolo, Vanesa Gottifredi
The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/ 10.1016/j.mrfmmm.2017.09.006. This duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
September 25, 2017: Mutation Research
https://www.readbyqxmd.com/read/28938540/microrna-128-3p-regulates-mitomycin-c-induced-dna-damage-response-in-lung-cancer-cells-through-repressing-sptan1
#9
Rui Zhang, Chang Liu, Yahan Niu, Ying Jing, Haiyang Zhang, Jin Wang, Jie Yang, Ke Zen, Junfeng Zhang, Chen-Yu Zhang, Donghai Li
The DNA damage response is critical for maintaining genome integrity and preventing damage to DNA due to endogenous and exogenous insults. Mitomycin C (MMC), a potent DNA cross-linker, is used as a chemotherapeutic agent because it causes DNA inter-strand cross-links (DNA ICLs) in cancer cells. While many microRNAs, which may serve as oncogenes or tumor suppressors, are grossly dysregulated in human cancers, little is known about their roles in MMC-treated lung cancer. Here, we report that miR-128-3p can attenuate repair of DNA ICLs by targeting SPTAN1 (αII Sp), resulting in cell cycle arrest and promoting chromosomal aberrations in lung cancer cells treated with MMC...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28937154/structural-basis-of-interstrand-cross-link-repair-by-o-6-alkylguanine-dna-alkyltransferase
#10
Alexey Y Denisov, Francis P McManus, Derek K O'Flaherty, Anne M Noronha, Christopher J Wilds
DNA interstrand cross-links (ICL) are among the most cytotoxic lesions found in biological systems. O(6)-Alkylguanine DNA alkyltransferases (AGTs) are capable of removing alkylation damage from the O(6)-atom of 2'-deoxyguanosine and the O(4)-atom of thymidine. Human AGT (hAGT) has demonstrated the ability to repair an interstrand cross-linked duplex where two O(6)-atoms of 2'-deoxyguanosine were tethered by a butylene (XLGG4) or heptylene (XLGG7) linkage. However, the analogous ICL between the O(4)-atoms of thymidine was found to evade repair...
October 11, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28934497/systematic-analysis-of-dna-crosslink-repair-pathways-during-development-and-aging-in-caenorhabditis-elegans
#11
David M Wilson, Matthias Rieckher, Ashley B Williams, Björn Schumacher
DNA interstrand crosslinks (ICLs) are generated by endogenous sources and chemotherapeutics, and pose a threat to genome stability and cell survival. Using Caenorhabditis elegans mutants, we identify DNA repair factors that protect against the genotoxicity of ICLs generated by trioxsalen/ultraviolet A (TMP/UVA) during development and aging. Mutations in nucleotide excision repair (NER) components (e.g. XPA-1 and XPF-1) imparted extreme sensitivity to TMP/UVA relative to wild-type animals, manifested as developmental arrest, defects in adult tissue morphology and functionality, and shortened lifespan...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28855448/caffeine-has-a-synergistic-anticancer-effect-with-cisplatin-via-inhibiting-fanconi-anemia-group-d2-protein-monoubiquitination-in-hepatocellular-carcinoma-cells
#12
Yuichiro Oda, Muneaki Hidaka, Akito Suzuki
Cisplatin is an anticancer agent and induces DNA interstrand cross-links (ICLs). ICLs activate various signaling processes and induce DNA repair pathways, including the Fanconi anemia (FA) pathway. FA complementation group D2 (FANCD2) is monoubiquitinated in response to DNA damage, leading to activation of the DNA double-strand-break repair protein, RAD51. Caffeine increases the anticancer activity of cisplatin by inhibiting DNA repair; however, details of the mechanism remain unclear. We investigated the mechanism responsible for the synergistic anticancer effect of cisplatin and caffeine in HepG2 human hepatocellular carcinoma cells, focusing on the FA pathway...
August 31, 2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28792090/distinct-activation-mechanisms-trigger-the-trypanocidal-activity-of-dna-damaging-prodrugs
#13
Emma Louise Meredith, Ambika Kumar, Aya Konno, Joanna Szular, Sam Alsford, Karin Seifert, David Horn, Shane R Wilkinson
Quinone-based compounds have been exploited to treat infectious diseases and cancer, with such chemicals often functioning as inhibitors of key metabolic pathways or as prodrugs. Here, we screened an aziridinyl 1,4-benzoquinone (ABQ) library against the causative agents of trypanosomiasis, and cutaneous leishmaniasis, identifying several potent structures that exhibited EC50 values of <100 nM. However, these compounds also displayed significant toxicity towards mammalian cells indicating that they are not suitable therapies for systemic infections...
October 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28687272/interstrand-crosslink-repair-as-a-target-for-hdac-inhibition
#14
REVIEW
Teodora Nikolova, Nicole Kiweler, Oliver H Krämer
DNA interstrand crosslinks (ICLs) covalently connect complementary DNA strands. Consequently, DNA replication and transcription are hampered, DNA damage responses (DDR) are initiated, and cell death is triggered. Therefore, drugs inducing ICLs are effective against rapidly growing cancer cells. However, tumors engage a complicated enzymatic machinery to repair and survive ICLs. Several factors, including the post-translational acetylation/deacetylation of lysine residues within proteins, control this network...
September 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28684355/studies-of-protein-protein-interactions-in-fanconi-anemia-pathway-to-unravel-the-dna-interstrand-crosslink-repair-mechanism
#15
Mohd Quadir Siddiqui, Yogendra S Rajpurohit, Pankaj S Thapa, Ganesh Kumar Maurya, Kuheli Banerjee, Mudassar Ali Khan, Pragnya Panda, Syed K Hasan, Nikhil Gadewal, Hari S Misra, Ashok K Varma
Fanconi anemia (FA), a cancer predisposition syndrome exhibits hallmark feature of radial chromosome formation, and hypersensitivity to DNA crosslinking agents. A set of FA pathway proteins mainly FANCI, FANCD2 and BRCA2 are expressed to repair the covalent crosslink between the dsDNA. However, FA, BRCA pathways play an important role in DNA ICL repair as well as in homologous recombination repair, but the presumptive role of FA-BRCA proteins has not clearly explored particularly in context to function associated protein-protein interactions (PPIs)...
November 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28654754/potential-strategies-to-target-protein-protein-interactions-in-the-dna-damage-response-and-repair-pathways
#16
Naoaki Fujii
This review article discusses some insights about generating novel mechanistic inhibitors of the DNA damage response and repair (DDR) pathways by focusing on protein-protein interactions (PPIs) of the key DDR components. General requirements for PPI strategies, such as selecting the target PPI site on the basis of its functionality, are discussed first. Next, on the basis of functional rationale and biochemical feasibility to identify a PPI inhibitor, 26 PPIs in DDR pathways (BER, MMR, NER, NHEJ, HR, TLS, and ICL repair) are specifically discussed for inhibitor discovery to benefit cancer therapies using a DNA-damaging agent...
July 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28645378/preparation-of-stable-nitrogen-mustard-dna-interstrand-cross-link-analogs-for-biochemical-and-cell-biological-studies
#17
Alejandra Castaño, Upasana Roy, Orlando D Schärer
Nitrogen mustards (NMs) react with two bases on opposite strands of a DNA duplex to form a covalent linkage, yielding adducts called DNA interstrand cross-links (ICLs). This prevents helix unwinding, blocking essential processes such as replication and transcription. Accumulation of ICLs causes cell death in rapidly dividing cells, especially cancer cells, making ICL-forming agents like NMs valuable in chemotherapy. However, the repair of ICLs can contribute to chemoresistance through a number of pathways that remain poorly understood...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28634400/chronic-treatment-with-cisplatin-induces-chemoresistance-through-the-tip60-mediated-fanconi-anemia-and-homologous-recombination-repair-pathways
#18
Wen-Pin Su, Yen-Chih Ho, Cheng-Kuei Wu, Sen-Huei Hsu, Jia-Lin Shiu, Jheng-Cheng Huang, Song-Bin Chang, Wen-Tai Chiu, Jan-Jong Hung, Tsung-Lin Liu, Wei-Sheng Wu, Pei-Yu Wu, Wu-Chou Su, Jang-Yang Chang, Hungjiun Liaw
The Fanconi anemia pathway in coordination with homologous recombination is essential to repair interstrand crosslinks (ICLs) caused by cisplatin. TIP60 belongs to the MYST family of acetyltransferases and is involved in DNA repair and regulation of gene transcription. Although the physical interaction between the TIP60 and FANCD2 proteins has been identified that is critical for ICL repair, it is still elusive whether TIP60 regulates the expression of FA and HR genes. In this study, we found that the chemoresistant nasopharyngeal carcinoma cells, derived from chronic treatment of cisplatin, show elevated expression of TIP60...
June 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28627616/distinct-cellular-phenotype-linked-to-defective-dna-interstrand-crosslink-repair-and-homologous-recombination
#19
Aleksandra M Gorniewska, Katarzyna Kluzek, Lidia Gackowska, Izabela Kubiszewska, Malgorzata Z Zdzienicka, Aneta Bialkowska
Repair of DNA interstrand crosslinks (ICLs) predominantly involves the Fanconi anemia (FA) pathway and homologous recombination (HR). The HR repair system eliminates DNA double strand breaks (DSBs) that emerge during ICLs removal. The current study presents a novel cell line, CL‑V8B, representing a new complementation group of Chinese hamster cell mutants hypersensitive to DNA crosslinking factors. CL‑V8B exhibits increased sensitivity to various DNA‑damaging agents, including compounds leading to DSBs formation (bleomycin and 6‑thioguanine), and is extremely sensitive to poly (ADP-ribose) polymerase inhibitor (>400‑fold), which is typical for HR‑defective cells...
August 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28627569/porphyrin-based-photosensitizers-and-their-dna-conjugates-for-singlet-oxygen-induced-nucleic-acid-interstrand-crosslinking
#20
Eva M Llamas, João P C Tome, João M M Rodrigues, Tomás Torres, Annemieke Madder
The development of methods for the generation of site-selective interstrand crosslinks (ICLs) in synthetic oligonucleotides provides a platform for the study of ICL repair mechanisms and the stabilisation of DNA-based materials. Our group has previously reported on the use of a furan moiety as a masked reactive functionality for ICL generation and recently introduced the use of (1)O2 as an efficient light-induced oxidant. Here, the use of porphyrin-based photosensitizers (PSs) has been explored for ICL generation...
June 27, 2017: Organic & Biomolecular Chemistry
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