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Julie Reygner, Lydia Lichtenberger, Ghada Elmhiri, Samir Dou, Narges Bahi-Jaber, Larbi Rhazi, Flore Depeint, Veronique Bach, Hafida Khorsi-Cauet, Latifa Abdennebi-Najar
Increasing evidence indicates that chlorpyrifos (CPF), an organophosphorus insecticide, is involved in metabolic disorders. We assess the hypothesis whether supplementation with prebiotics from gestation to adulthood, through a modulation of microbiota composition and fermentative activity, alleviates CPF induced metabolic disorders of 60 days old offspring. 5 groups of Wistar rats, from gestation until weaning, received two doses of CPF pesticide: 1 mg/kg/day (CPF1) or 3.5 mg/kg/day (CPF3.5) with free access to inulin (10g/L in drinking water)...
2016: PloS One
Alexandra East-Seletsky, Mitchell R O'Connell, Spencer C Knight, David Burstein, Jamie H D Cate, Robert Tjian, Jennifer A Doudna
Bacterial adaptive immune systems use CRISPRs (clustered regularly interspaced short palindromic repeats) and CRISPR-associated (Cas) proteins for RNA-guided nucleic acid cleavage. Although most prokaryotic adaptive immune systems generally target DNA substrates, type III and VI CRISPR systems direct interference complexes against single-stranded RNA substrates. In type VI systems, the single-subunit C2c2 protein functions as an RNA-guided RNA endonuclease (RNase). How this enzyme acquires mature CRISPR RNAs (crRNAs) that are essential for immune surveillance and how it carries out crRNA-mediated RNA cleavage remain unclear...
September 26, 2016: Nature
Eszter Tóth, Nóra Weinhardt, Petra Bencsura, Krisztina Huszár, Péter I Kulcsár, András Tálas, Elfrieda Fodor, Ervin Welker
BACKGROUND: Cpf1 nucleases have recently been repurposed for site-specific genome modification. Two members of the Cpf1 family, the AsCpf1 from Acidaminococcus sp. and the LbCpf1 from Lachnospiraceae bacterium were shown to induce higher indel frequencies than SpCas9 when examining four randomly-selected target sequences for each type of nuclease. Whether they are a real match for Cas9 nucleases, however, remains to be verified. RESULTS: Here, we used AsCpf1 and LbCpf1 to induce homology directed repair, either single strand annealing (SSA) or homologous recombination (HR), in N2a mouse neuroblastoma cells...
2016: Biology Direct
Fillip Port, Simon L Bullock
We present tRNA-based vectors for producing multiple clustered regularly interspaced short palindromic repeats (CRISPR) single guide RNAs (sgRNAs) from a single RNA polymerase II or III transcript in Drosophila. The system, which is based on liberation of sgRNAs by processing flanking tRNAs, permits highly efficient multiplexing of Cas9-based mutagenesis. We also demonstrate that the tRNA-sgRNA system markedly increases the efficacy of conditional gene disruption by Cas9 and can promote editing by the recently discovered RNA-guided endonuclease Cpf1...
October 2016: Nature Methods
W Darwiche, S Delanaud, S Dupont, H Ghamlouch, W Ramadan, W Joumaa, V Bach, J Gay-Quéheillard
BACKGROUND: Prenatal/postnatal exposure to insecticides has been linked to developmental disorders in adulthood. Chlorpyrifos (CPF) is a widely used organophosphorus acetylcholinesterase (AChE)-inhibiting insecticide. The present study established whether prenatal and postnatal exposure to CPF is associated with intestinal motor dysfunction in adult rats. METHODS: Three groups of pregnant rats were exposed to either CPF (1 or 5 mg/kg/day; the CPF1 and CPF5 groups) or vehicle (the control group) by gavage from gestational day 1 until weaning...
August 21, 2016: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Daesik Kim, Jungeun Kim, Junho K Hur, Kyung Wook Been, Sun-Heui Yoon, Jin-Soo Kim
No abstract text is available yet for this article.
August 9, 2016: Nature Biotechnology
Pu Gao, Hui Yang, Kanagalaghatta R Rajashankar, Zhiwei Huang, Dinshaw J Patel
CRISPR-Cas9 and CRISPR-Cpf1 systems have been successfully harnessed for genome editing. In the CRISPR-Cas9 system, the preordered A-form RNA seed sequence and preformed protein PAM-interacting cleft are essential for Cas9 to form a DNA recognition-competent structure. Whether the CRISPR-Cpf1 system employs a similar mechanism for target DNA recognition remains unclear. Here, we have determined the crystal structure of Acidaminococcus sp. Cpf1 (AsCpf1) in complex with crRNA and target DNA. Structural comparison between the AsCpf1-crRNA-DNA ternary complex and the recently reported Lachnospiraceae bacterium Cpf1 (LbCpf1)-crRNA binary complex identifies a unique mechanism employed by Cpf1 for target recognition...
August 2016: Cell Research
Benjamin P Kleinstiver, Shengdar Q Tsai, Michelle S Prew, Nhu T Nguyen, Moira M Welch, Jose M Lopez, Zachary R McCaw, Martin J Aryee, J Keith Joung
The activities and genome-wide specificities of CRISPR-Cas Cpf1 nucleases are not well defined. We show that two Cpf1 nucleases from Acidaminococcus sp. BV3L6 and Lachnospiraceae bacterium ND2006 (AsCpf1 and LbCpf1, respectively) have on-target efficiencies in human cells comparable with those of the widely used Streptococcus pyogenes Cas9 (SpCas9). We also report that four to six bases at the 3' end of the short CRISPR RNA (crRNA) used to program Cpf1 nucleases are insensitive to single base mismatches, but that many of the other bases in this region of the crRNA are highly sensitive to single or double substitutions...
August 2016: Nature Biotechnology
Shi-Yuan Li, Guo-Ping Zhao, Jin Wang
So far, several DNA assembly standards have been developed, enabling scientists to conveniently share and modify characterized DNA parts. However, a majority of the restriction endonucleases used in these standards bear short recognition sites (e.g., 6 bps in BioBrick standard), which are widely distributed and need to be removed before further construction, causing much inconvenience. Although homing endonucleases, which recognize long DNA sequences, can be used for DNA assembly (e.g., iBrick standard), long scars will be left between parts, limiting their application...
June 17, 2016: ACS Synthetic Biology
Yongsub Kim, Seung-A Cheong, Jong Geol Lee, Sang-Wook Lee, Myeong Sup Lee, In-Jeoung Baek, Young Hoon Sung
No abstract text is available yet for this article.
August 2016: Nature Biotechnology
Junho K Hur, Kyoungmi Kim, Kyung Wook Been, Gayoung Baek, Sunghyeok Ye, Junseok W Hur, Seuk-Min Ryu, Youn Su Lee, Jin-Soo Kim
No abstract text is available yet for this article.
August 2016: Nature Biotechnology
Daesik Kim, Jungeun Kim, Junho K Hur, Kyung Wook Been, Sun-Heui Yoon, Jin-Soo Kim
Programmable clustered regularly interspaced short palindromic repeats (CRISPR) Cpf1 endonucleases are single-RNA-guided (crRNA) enzymes that recognize thymidine-rich protospacer-adjacent motif (PAM) sequences and produce cohesive double-stranded breaks (DSBs). Genome editing with CRISPR-Cpf1 endonucleases could provide an alternative to CRISPR-Cas9 endonucleases, but the determinants of targeting specificity are not well understood. Using mismatched crRNAs we found that Cpf1 could tolerate single or double mismatches in the 3' PAM-distal region, but not in the 5' PAM-proximal region...
August 2016: Nature Biotechnology
Maximilian Haeussler, Jean-Paul Concordet
The CRISPR-Cas revolution is taking place in virtually all fields of life sciences. Harnessing DNA cleavage with the CRISPR-Cas9 system of Streptococcus pyogenes has proven to be extraordinarily simple and efficient, relying only on the design of a synthetic single guide RNA (sgRNA) and its co-expression with Cas9. Here, we review the progress in the design of sgRNA from the original dual RNA guide for S. pyogenes and Staphylococcus aureus Cas9 (SpCas9 and SaCas9). New assays for genome-wide identification of off-targets have provided important insights into the issue of cleavage specificity in vivo...
May 20, 2016: Journal of Genetics and Genomics, Yi Chuan Xue Bao
Kornel Labun, Tessa G Montague, James A Gagnon, Summer B Thyme, Eivind Valen
In just 3 years CRISPR genome editing has transformed biology, and its popularity and potency continue to grow. New CRISPR effectors and rules for locating optimum targets continue to be reported, highlighting the need for computational CRISPR targeting tools to compile these rules and facilitate target selection and design. CHOPCHOP is one of the most widely used web tools for CRISPR- and TALEN-based genome editing. Its overarching principle is to provide an intuitive and powerful tool that can serve both novice and experienced users...
July 8, 2016: Nucleic Acids Research
Malcolm F White
No abstract text is available yet for this article.
May 4, 2016: Nature Structural & Molecular Biology
Naomi Attar
No abstract text is available yet for this article.
June 2016: Nature Reviews. Microbiology
Takashi Yamano, Hiroshi Nishimasu, Bernd Zetsche, Hisato Hirano, Ian M Slaymaker, Yinqing Li, Iana Fedorova, Takanori Nakane, Kira S Makarova, Eugene V Koonin, Ryuichiro Ishitani, Feng Zhang, Osamu Nureki
Cpf1 is an RNA-guided endonuclease of a type V CRISPR-Cas system that has been recently harnessed for genome editing. Here, we report the crystal structure of Acidaminococcus sp. Cpf1 (AsCpf1) in complex with the guide RNA and its target DNA at 2.8 Å resolution. AsCpf1 adopts a bilobed architecture, with the RNA-DNA heteroduplex bound inside the central channel. The structural comparison of AsCpf1 with Cas9, a type II CRISPR-Cas nuclease, reveals both striking similarity and major differences, thereby explaining their distinct functionalities...
May 5, 2016: Cell
De Dong, Kuan Ren, Xiaolin Qiu, Jianlin Zheng, Minghui Guo, Xiaoyu Guan, Hongnan Liu, Ningning Li, Bailing Zhang, Daijun Yang, Chuang Ma, Shuo Wang, Dan Wu, Yunfeng Ma, Shilong Fan, Jiawei Wang, Ning Gao, Zhiwei Huang
The CRISPR-Cas systems, as exemplified by CRISPR-Cas9, are RNA-guided adaptive immune systems used by bacteria and archaea to defend against viral infection. The CRISPR-Cpf1 system, a new class 2 CRISPR-Cas system, mediates robust DNA interference in human cells. Although functionally conserved, Cpf1 and Cas9 differ in many aspects including their guide RNAs and substrate specificity. Here we report the 2.38 Å crystal structure of the CRISPR RNA (crRNA)-bound Lachnospiraceae bacterium ND2006 Cpf1 (LbCpf1)...
April 28, 2016: Nature
Ines Fonfara, Hagen Richter, Majda Bratovič, Anaïs Le Rhun, Emmanuelle Charpentier
CRISPR-Cas systems that provide defence against mobile genetic elements in bacteria and archaea have evolved a variety of mechanisms to target and cleave RNA or DNA. The well-studied types I, II and III utilize a set of distinct CRISPR-associated (Cas) proteins for production of mature CRISPR RNAs (crRNAs) and interference with invading nucleic acids. In types I and III, Cas6 or Cas5d cleaves precursor crRNA (pre-crRNA) and the mature crRNAs then guide a complex of Cas proteins (Cascade-Cas3, type I; Csm or Cmr, type III) to target and cleave invading DNA or RNA...
April 28, 2016: Nature
Ryan T Leenay, Kenneth R Maksimchuk, Rebecca A Slotkowski, Roma N Agrawal, Ahmed A Gomaa, Alexandra E Briner, Rodolphe Barrangou, Chase L Beisel
CRISPR-Cas adaptive immune systems in prokaryotes boast a diversity of protein families and mechanisms of action, where most systems rely on protospacer-adjacent motifs (PAMs) for DNA target recognition. Here, we developed an in vivo, positive, and tunable screen termed PAM-SCANR (PAM screen achieved by NOT-gate repression) to elucidate functional PAMs as well as an interactive visualization scheme termed the PAM wheel to convey individual PAM sequences and their activities. PAM-SCANR and the PAM wheel identified known functional PAMs while revealing complex sequence-activity landscapes for the Bacillus halodurans I-C (Cascade), Escherichia coli I-E (Cascade), Streptococcus thermophilus II-A CRISPR1 (Cas9), and Francisella novicida V-A (Cpf1) systems...
April 7, 2016: Molecular Cell
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