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Manaswita Jain, Rainer W J Kaiser, Katrin Bohl, Martin Hoehne, Heike Göbel, Malte P Bartram, Sandra Habbig, Roman-Ulrich Müller, Agnes B Fogo, Thomas Benzing, Bernhard Schermer, Katja Höpker, Gisela G Slaats
Recent human genetic studies have suggested an intriguing link between ciliary signaling defects and altered DNA damage responses in nephronophthisis (NPH) and related ciliopathies. However, the molecular mechanism and the role of altered DNA damage response in kidney degeneration and fibrosis have remained elusive. We recently identified the kinase-regulated DNA damage response target Apoptosis Antagonizing Transcription Factor (AATF) as a master regulator of the p53 response. Here, we characterized the phenotype of mice with genetic deletion of Aatf in tubular epithelial cells...
February 12, 2019: Kidney International
Madzia P Crossley, Michael Bocek, Karlene A Cimprich
During transcription, the nascent RNA strand can base pair with its template DNA, displacing the non-template strand as ssDNA and forming a structure called an R-loop. R-loops are common across many domains of life and cause DNA damage in certain contexts. In this review, we summarize recent results implicating R-loops as important regulators of cellular processes such as transcription termination, gene regulation, and DNA repair. We also highlight recent work suggesting that R-loops can be problematic to cells as blocks to efficient transcription and replication that trigger the DNA damage response...
February 7, 2019: Molecular Cell
Jun Katahira, Hiroki Ishikawa, Kakeru Tsujimura, Sadamu Kurono, Miki Hieda
A multiprotein complex, THO/TREX, couples the transcription, 3'-end formation, and nuclear export of mRNAs. In this study, we report that crucial factors for mRNA processing, such as XRN2, DDX5/DDX17, and CstF64, are copurified with human THO (hTHO). Using chromatin immunoprecipitation, we found increased cross-linking of XRN2 and CstF64 to the RNA polymerase II (RNAP II) pause site of the HSPA1A gene upon downregulation of THOC5, a metazoan-specific component of hTHO. As observed in THOC5-depleted cells, knockdown of XRN2 blocked HSP70 transcript release and increased the amount of CstF64 at the pause site...
February 5, 2019: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Alberto Díaz-Talavera, Patricia A Calvo, Daniel González-Acosta, Marcos Díaz, Guillermo Sastre-Moreno, Luis Blanco-Franco, Susana Guerra, Maria I Martínez-Jiménez, Juan Méndez, Luis Blanco
PrimPol is a human primase/polymerase specialized in re-starting stalled forks by repriming beyond lesions such as pyrimidine dimers, and replication-perturbing structures including G-quadruplexes and R-loops. Unlike most conventional primases, PrimPol proficiently discriminates against ribonucleotides (NTPs), being able to start synthesis using deoxynucleotides (dNTPs), yet the structural basis and physiological implications for this discrimination are not understood. In silico analyses based on the three-dimensional structure of human PrimPol and related enzymes enabled us to predict a single residue, Tyr100 , as the main effector of sugar discrimination in human PrimPol and a change of Tyr100 to histidine to boost the efficiency of NTP incorporation...
February 4, 2019: Scientific Reports
Konstantina Skourti-Stathaki, Elena Torlai Triglia, Marie Warburton, Philipp Voigt, Adrian Bird, Ana Pombo
R-loops are three-stranded nucleic acid structures that form during transcription, especially over unmethylated CpG-rich promoters of active genes. In mouse embryonic stem cells (mESCs), CpG-rich developmental regulator genes are repressed by the Polycomb complexes PRC1 and PRC2. Here, we show that R-loops form at a subset of Polycomb target genes, and we investigate their contribution to Polycomb repression. At R-loop-positive genes, R-loop removal leads to decreased PRC1 and PRC2 recruitment and Pol II activation into a productive elongation state, accompanied by gene derepression at nascent and processed transcript levels...
January 14, 2019: Molecular Cell
Vladimir Mekler, Konstantin Kuznedelov, Leonid Minakhin, Karthik Murugan, Dipali G Sashital, Konstantin Severinov
CRISPR-Cas systems protect prokaryotic cells from invading phages and plasmids by recognizing and cleaving foreign nucleic acid sequences specified by CRISPR RNA spacer sequences. Several CRISPR-Cas systems have been widely used as tool for genetic engineering. In DNA-targeting CRISPR-Cas nucleoprotein effector complexes, the CRISPR RNA forms a hybrid with the complementary strand of foreign DNA, displacing the noncomplementary strand to form an R-loop. The DNA interrogation and R-loop formation involve several distinct steps the molecular details of which are not fully understood...
2019: Methods in Enzymology
Yibei Xiao, Ailong Ke
Type I CRISPR-Cas, the most prevalent CRISPR system, features a sequential target searching and degradation process. First, the multisubunit surveillance complex Cascade recognizes the matching dsDNA target flanked by protospacer adjacent motif (PAM), promotes the heteroduplex formation between CRISPR RNA (crRNA) and the target strand (TS) DNA, and displaces the nontarget strand (NTS) DNA, resulting in R-loop formation. The helicase-nuclease fusion enzyme Cas3 is then specifically recruited to Cascade/R-loop, nicks, and processively degrades the DNA target...
2019: Methods in Enzymology
Huiyuan Wang, Huihui Wang, Hangxiao Zhang, Sheng Liu, Yongsheng Wang, Yubang Gao, Feihu Xi, Liangzhen Zhao, Bo Liu, Anireddy S N Reddy, Chentao Lin, Lianfeng Gu
Motivation: MicroRNA (miRNA) and alternative splicing (AS)-mediated post-transcriptional regulation has been extensively studied in most eukaryotes. However, the interplay between AS and miRNAs has not been explored in plants. To our knowledge, the overall profile of miRNA target sites in circular RNAs (circRNA) generated by alternative back splicing has never been reported previously. To address the challenge, we identified miRNA target sites located in alternatively spliced regions of the linear and circular splice isoforms using the up-to-date single-molecule real-time (SMRT) isoform sequencing (Iso-Seq) and Illumina sequencing data in eleven plant species...
January 24, 2019: Bioinformatics
(no author information available yet)
GADD45A binding to R-loops promotes TET1 recruitment and DNA demethylation at CpG island promoters.
January 18, 2019: Cancer Discovery
Maria Marín, María José Ramírez, Miriam Aza Carmona, Nan Jia, Tomoo Ogi, Massimo Bogliolo, Jordi Surrallés
XPF endonuclease is one of the most important DNA repair proteins. Encoded by XPF / ERCC4 , XPF provides the enzymatic activity of XPF-ERCC1 heterodimer, an endonuclease that incises at the 5' side of various DNA lesions. XPF is essential for nucleotide excision repair (NER) and interstrand crosslink repair (ICLR). XPF / ERCC4 mutations are associated with several human diseases: Xeroderma Pigmentosum (XP), Segmental Progeria (XFE), Fanconi Anemia (FA), Cockayne Syndrome (CS), and XP/CS combined disease (XPCSCD)...
January 17, 2019: Genes
Veronica Marabitti, Giorgia Lillo, Eva Malacaria, Valentina Palermo, Massimo Sanchez, Pietro Pichierri, Annapaola Franchitto
Werner syndrome (WS) is a cancer-prone disease caused by deficiency of Werner protein (WRN). WRN maintains genome integrity by promoting replication-fork stability after various forms of replication stress. Under mild replication stress, WS cells show impaired ATR-mediated CHK1 activation. However, it remains unclear if WS cells elicit other repair pathway. We demonstrate that loss of WRN leads to enhanced ATM phosphorylation upon prolonged exposure to aphidicolin, a specific inhibitor of DNA polymerases, resulting in CHK1 activation...
January 18, 2019: Nucleic Acids Research
Maddalen Jiménez, Raquel Urtasun, María Elizalde, María Azkona, M Ujue Latasa, Iker Uriarte, María Arechederra, Diego Alignani, Marina Bárcena-Varela, Gloria Álvarez-Sola, Leticia Colyn, Eva Santamaría, Bruno Sangro, Carlos Rodriguez-Ortigosa, Maite G Fernández-Barrena, Matías A Ávila, Carmen Berasain
Genome instability is related to disease development and carcinogenesis. DNA lesions are caused by genotoxic compounds but also by the dysregulation of fundamental processes like transcription, DNA replication and mitosis. Recent evidence indicates that impaired expression of RNA-binding proteins results in mitotic aberrations and the formation of transcription-associated RNA-DNA hybrids (R-loops), events strongly associated with DNA injury. We identify the splicing regulator SLU7 as a key mediator of genome stability...
January 18, 2019: Nucleic Acids Research
Zhuobin Liang, Fengshan Liang, Yaqun Teng, Xiaoyong Chen, Jingchun Liu, Simonne Longerich, Timsi Rao, Allison M Green, Natalie B Collins, Yong Xiong, Li Lan, Patrick Sung, Gary M Kupfer
Fanconi anemia (FA) is characterized by developmental abnormalities, bone marrow failure, and cancer predisposition. FA cells are hypersensitive to DNA replicative stress and accumulate co-transcriptional R-loops. Here, we use the Damage At RNA Transcription assay to reveal colocalization of FANCD2 with R-loops in a highly transcribed genomic locus upon DNA damage. We further demonstrate that highly purified human FANCI-FANCD2 (ID2) complex binds synthetic single-stranded RNA (ssRNA) and R-loop substrates with high affinity, preferring guanine-rich sequences...
January 15, 2019: Cell Reports
S R Catford, M K O'Bryan, R I McLachlan, M B Delatycki, L Rombauts
Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive neurodegenerative disorder characterized by cerebellar atrophy, peripheral neuropathy and oculomotor apraxia. It is caused by mutations in the SETX gene that encodes senataxin, a ubiquitously expressed protein that mediates processes, including transcription, transcription termination, DNA repair, RNA processing, DNA-RNA hybrid (R-loop) elimination and telomere stability. In mice, senataxin is essential for male germ cell development and fertility through its role in meiotic recombination and sex chromosome inactivation...
January 9, 2019: Reproductive Biomedicine Online
Sushree Tripathy, Wenjun Zheng, Anthony Auerbach
Agonists turn on receptors because they bind more strongly to active (R*) versus resting (R) conformations of their target sites. Here, to explore how agonists activate neuromuscular acetylcholine receptors, we built homology models of R and R* neurotransmitter binding sites, docked ligands to those sites, ran molecular dynamics simulations to relax ("equilibrate") the structures, measured binding site structural parameters, and correlated them with experimental agonist binding energies. Each binding pocket is a pyramid formed by five aromatic amino acids and covered partially by loop C...
January 11, 2019: Journal of General Physiology
Chen Zhang, Hang Fu, Yajun Yang, Erchi Zhou, Zhijie Tan, Huijuan You, Xinghua Zhang
RNA can anneal to its DNA template to generate an RNA-DNA hybrid (RDH) duplex and a displaced DNA strand, termed R-loop. RDH duplex occupies up to 5% of the mammalian genome and plays important roles in many biological processes. The functions of RDH duplex are affected by its mechanical properties, including the elasticity and the conformation transitions. The mechanical properties of RDH duplex, however, are still unclear. In this work, we studied the mechanical properties of RDH duplex using magnetic tweezers in comparison with those of DNA and RNA duplexes with the same sequences...
December 13, 2018: Biophysical Journal
Khelifa Arab, Emil Karaulanov, Michael Musheev, Philipp Trnka, Andrea Schäfer, Ingrid Grummt, Christof Niehrs
R-loops are DNA-RNA hybrids enriched at CpG islands (CGIs) that can regulate chromatin states1-8 . How R-loops are recognized and interpreted by specific epigenetic readers is unknown. Here we show that GADD45A (growth arrest and DNA damage protein 45A) binds directly to R-loops and mediates local DNA demethylation by recruiting TET1 (ten-eleven translocation 1). Studying the tumor suppressor TCF21 (ref. 9 ), we find that antisense long noncoding (lncRNA) TARID (TCF21 antisense RNA inducing promoter demethylation) forms an R-loop at the TCF21 promoter...
January 7, 2019: Nature Genetics
Viktor Posse, Ali Al-Behadili, Jay P Uhler, Anders R Clausen, Aurelio Reyes, Massimo Zeviani, Maria Falkenberg, Claes M Gustafsson
Human mitochondrial DNA (mtDNA) replication is first initiated at the origin of H-strand replication. The initiation depends on RNA primers generated by transcription from an upstream promoter (LSP). Here we reconstitute this process in vitro using purified transcription and replication factors. The majority of all transcription events from LSP are prematurely terminated after ~120 nucleotides, forming stable R-loops. These nascent R-loops cannot directly prime mtDNA synthesis, but must first be processed by RNase H1 to generate 3'-ends that can be used by DNA polymerase γ to initiate DNA synthesis...
January 2019: PLoS Genetics
László Halász, Zsolt Karányi, Beáta Boros-Oláh, Tímea Kuik-Rózsa, Éva Sipos, Éva Nagy, Ágnes Mosolygó-L, Anett Mázló, Éva Rajnavölgyi, Gábor Halmos, Lóránt Székvölgyi
No abstract text is available yet for this article.
January 2019: Genome Research
Azin Alizadehasl, Mohammad Ali Akbarzadeh, Anita Sadeghpour, Majid Haghjoo, Behshid Ghadrdoost, Mahbubeh Zeighami, Arezoo Haghighat Talab
BACKGROUND: According to American Heart Association guidelines, QRS duration and morphology are used to select patients for cardiac resynchronization therapy (CRT). But still there are some patients who are not responding to this device. We investigated whether the Cardiogoniometry (CGM) as a three-dimensional vectorcardiogram method can improve patient selection. METHODS: Echocardiography and CGM were performed for 25 consecutive patients with Left bundle branch morphology who were candidate for CRT implantation and were in sinus rhythm...
December 2018: Indian Heart Journal
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