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https://www.readbyqxmd.com/read/29590434/an-e2f7-dependent-transcriptional-program-modulates-dna-damage-repair-and-genomic-stability
#1
Jone Mitxelena, Aintzane Apraiz, Jon Vallejo-Rodríguez, Iraia García-Santisteban, Asier Fullaondo, Mónica Alvarez-Fernández, Marcos Malumbres, Ana M Zubiaga
The cellular response to DNA damage is essential for maintaining the integrity of the genome. Recent evidence has identified E2F7 as a key player in DNA damage-dependent transcriptional regulation of cell-cycle genes. However, the contribution of E2F7 to cellular responses upon genotoxic damage is still poorly defined. Here we show that E2F7 represses the expression of genes involved in the maintenance of genomic stability, both throughout the cell cycle and upon induction of DNA lesions that interfere with replication fork progression...
March 24, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29557213/spectrin-and-its-interacting-partners-in-nuclear-structure-and-function
#2
Muriel W Lambert
Nonerythroid αII-spectrin is a structural protein whose roles in the nucleus have just begun to be explored. αII-spectrin is an important component of the nucleoskelelton and has both structural and non-structural functions. Its best known role is in repair of DNA ICLs both in genomic and telomeric DNA. αII-spectrin aids in the recruitment of repair proteins to sites of damage and a proposed mechanism of action is presented. It interacts with a number of different groups of proteins in the nucleus, indicating it has roles in additional cellular functions...
March 2018: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/29514982/structural-mechanism-of-dna-interstrand-cross-link-unhooking-by-the-bacterial-fan1-nuclease
#3
Hyeonseok Jin, Upasana Roy, Gwangrog Lee, Orlando D Schärer, Yunje Cho
DNA interstrand cross-links (ICLs) block the progress of the replication and transcription machineries and can weaken chromosomal stability, resulting in various diseases. FANCD2-FANCI-associated nuclease (FAN1) is a conserved structure-specific nuclease that unhooks DNA ICLs independently of the Fanconi anemia pathway. Recent structural studies have proposed two different mechanistic features for ICL unhooking by human FAN1: a specific basic pocket that recognizes the terminal phosphate of a 1-nucleotide (nt) 5' flap or FAN1 dimerization...
April 27, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29423082/reduced-recruitment-of-53bp1-during-interstrand-crosslink-repair-is-associated-with-genetically-inherited-attenuation-of-mitomycin-c-sensitivity-in-a-family-with-fanconi-anemia
#4
Emilie Lesport, Alina Ferster, Armand Biver, Benoit Roch, Nadia Vasquez, Nada Jabado, Francina Langa Vives, Patrick Revy, Jean Soulier, Jean-Pierre de Villartay
The Fanconi anemia (FA) pathway is implicated in the repair of DNA interstrand crosslinks (ICL). In this process, it has been shown that FA factors regulate the choice for DNA double strand break repair towards homologous recombination (HR). As this mechanism is impaired in FA deficient cells exposed to crosslinking agents, an inappropriate usage of non-homologous end joining (NHEJ) leads to the accumulation of toxic chromosomal abnormalities. We studied a family with two FANCG patients and found a genetically inherited attenuation of mitomycin C sensitivity resulting in-vitro in an attenuated phenotype for one patient or in increased resistance for two healthy relatives...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416673/splice-variants-of-the-endonucleases-xpf-and-xpg-contain-residual-dna-repair-capabilities-and-could-be-a-valuable-tool-for-personalized-medicine
#5
Janin Lehmann, Steffen Schubert, Christina Seebode, Antje Apel, Andreas Ohlenbusch, Steffen Emmert
The two endonucleases XPF and XPG are essentially involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. Defects in these two proteins result in severe diseases like xeroderma pigmentosum (XP). We applied our newly CRISPR/Cas9 generated human XPF knockout cell line with complete loss of XPF and primary fibroblasts from an XP-G patient (XP20BE) to analyze until now uncharacterized spontaneous mRNA splice variants of these two endonucleases. Functional analyses of these variants were performed using luciferase-based reporter gene assays...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29234069/the-human-dna-glycosylases-neil1-and-neil3-excise-psoralen-induced-dna-dna-cross-links-in-a-four-stranded-dna-structure
#6
Peter R Martin, Sophie Couvé, Caroline Zutterling, Mustafa S Albelazi, Regina Groisman, Bakhyt T Matkarimov, Jason L Parsons, Rhoderick H Elder, Murat K Saparbaev
Interstrand cross-links (ICLs) are highly cytotoxic DNA lesions that block DNA replication and transcription by preventing strand separation. Previously, we demonstrated that the bacterial and human DNA glycosylases Nei and NEIL1 excise unhooked psoralen-derived ICLs in three-stranded DNA via hydrolysis of the glycosidic bond between the crosslinked base and deoxyribose sugar. Furthermore, NEIL3 from Xenopus laevis has been shown to cleave psoralen- and abasic site-induced ICLs in Xenopus egg extracts. Here we report that human NEIL3 cleaves psoralen-induced DNA-DNA cross-links in three-stranded and four-stranded DNA substrates to generate unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29137116/altering-residue-134-confers-an-increased-substrate-range-of-alkylated-nucleosides-to-the-e-coli-ogt-protein
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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. O6 -Alkylguanine DNA alkyltransferases (AGTs) are capable of removing alkylation damage from the O6 -atom of 2'-deoxyguanosine and the O4 -atom of thymidine. Human AGT (hAGT) has demonstrated the ability to repair an interstrand cross-linked duplex where two O6 -atoms of 2'-deoxyguanosine were tethered by a butylene (XLGG4) or heptylene (XLGG7) linkage. However, the analogous ICL between the O4 -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
#17
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
#18
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
#19
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
#20
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
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