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A Minimal CRISPR-Cas3 System for Genome Engineering 2 Bálint Csörgő1,2*, Lina M

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A Minimal CRISPR-Cas3 System for Genome Engineering 2 Bálint Csörgő1,2*, Lina M bioRxiv preprint doi: https://doi.org/10.1101/860999; this version posted December 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 A minimal CRISPR-Cas3 system for genome engineering 2 Bálint Csörgő1,2*, Lina M. León1*, Ilea J. Chau-Ly3, Alejandro Vasquez-Rifo4, Joel D. Berry1, 3 Caroline Mahendra1, Emily D. Crawford1,5, Jennifer D. Lewis3,6, Joseph Bondy-Denomy1,7,8 4 1Department of Microbiology and Immunology, University of California, San Francisco, 94143, San Francisco, CA, USA 5 2Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany 6 3Department of Plant and Microbial Biology, University of California, Berkeley, 94720, Berkeley, CA, USA 7 4Program in Molecular Medicine, University of Massachusetts Medical School, 01605, Worcester, MA, USA 8 5Chan-Zuckerberg Biohub, 94158, San Francisco, CA, USA 9 6Plant Gene Expression Center, United States Department of Agriculture, Albany, CA 94710, USA 10 7Quantitative Biosciences Institute, University of California, San Francisco, 94143, San Francisco, CA, USA 11 8Innovative Genomics Institute 12 13 * Equal contribution 14 1 bioRxiv preprint doi: https://doi.org/10.1101/860999; this version posted December 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 15 Abstract 16 CRISPR-Cas technologies have provided programmable gene editing tools that have 17 revolutionized research. The leading CRISPR-Cas9 and Cas12a enzymes are ideal for 18 programmed genetic manipulation, however, they are limited for genome-scale interventions. 19 Here, we utilized a Cas3-based system featuring a processive nuclease, expressed 20 endogenously or heterologously, for genome engineering purposes. Using an optimized and 21 minimal CRISPR-Cas3 system (Type I-C) programmed with a single crRNA, large deletions 22 ranging from 7 - 424 kb were generated in Pseudomonas aeruginosa with high efficiency and 23 speed. By comparison, Cas9 yielded small deletions and point mutations. Cas3-generated 24 deletion boundaries were variable in the absence of a homology-directed repair (HDR) template, 25 and successfully and efficiently specified when present. The minimal Cas3 system is also 26 portable; large deletions were induced with high efficiency in Pseudomonas syringae and 27 Escherichia coli using an “all-in-one” vector. Notably, Cas3 generated bi-directional deletions 28 originating from the programmed cut site, which was exploited to iteratively reduce a P. 29 aeruginosa genome by 837 kb (13.5%) using 10 distinct crRNAs. We also demonstrate the utility 30 of endogenous Cas3 systems (Type I-C and I-F) and develop an “anti-anti-CRISPR” strategy to 31 circumvent endogenous CRISPR-Cas inhibitor proteins. CRISPR-Cas3 could facilitate rapid 32 strain manipulation for synthetic biological and metabolic engineering purposes, genome 33 minimization, and the analysis of large regions of unknown function. 34 2 bioRxiv preprint doi: https://doi.org/10.1101/860999; this version posted December 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 35 Introduction 36 CRISPR-Cas systems are a diverse group of RNA-guided nucleases1 that defend prokaryotes 37 against viral invaders2,3. Due to their relatively simple architecture, gene-editing applications have 38 focused on Class 2 CRISPR systems4 (i.e. Cas9 and Cas12a), but Class 1 systems hold great 39 potential for gene editing technologies, despite being more complex5–7. The signature gene in 40 Class 1 Type I systems is Cas3, a 3’-5’ ssDNA helicase-nuclease enzyme that, unlike Cas9 or 41 Cas12a, degrades target DNA processively5,6,8–13. This property of CRISPR-Cas3 systems raises 42 the possibility of its development as a tool for large genomic deletions. 43 44 Organisms from all domains of life contain vast segments of DNA that are poorly characterized, 45 of unknown function, or may be detrimental for fitness. In prokaryotes, these include prophages, 46 plasmids, and mobile islands, while in eukaryotes, large regions of repetitive sequences and non- 47 coding DNA are poorly characterized. Methods for generating programmable and rapid large 48 genomic deletions are needed for the study and engineering of these regions, however these are 49 currently inefficient14. A methodology that allows for targeted large genomic deletions in any host, 50 either with precisely programmed or random boundaries, would be broadly useful15. 51 52 Type I systems are the most prevalent CRISPR-Cas systems in nature1, which has enabled the 53 use of endogenous CRISPR-Cas3 systems for genetic manipulation via self-targeting. This has 54 been accomplished in Pectobacterium atrosepticum (Type I-F)16, Sulfolobus islandicus (Type I- 55 A)17, in various Clostridium species (Type I-B)18–20, and in Lactobacillus crispatus (Type I-E)21, 56 leading to deletions as large as 97 kb amongst the self-targeted survivor cells16. Additionally, two 57 recent studies have repurposed Type I systems for use in human cells, including the 58 ribonucleoprotein (RNP) based delivery of a Type I-E system22, and the use of I-E and I-B systems 59 for transcriptional modulation23. Here, we repurposed a Type I-C CRISPR system from 60 Pseudomonas aeruginosa for genome engineering in microbes. Importantly, by targeting the 61 genome with a single crRNA and selecting only for survival after editing, this tool is a counter- 62 selection-free approach to programmable genome editing. CRISPR-Cas3 is capable of efficient 63 genome-scale modifications currently not achievable using other methodologies. It has the 64 potential to serve as a powerful tool for basic research, discovery, and strain optimization. 65 66 Results 67 Implementation and optimization of genome editing with CRISPR-Cas3 68 Type I-C CRISPR-Cas systems utilize just three cas genes to produce the crRNA-guided 69 Cascade surveillance complex that can recruit Cas3: cas5, cas8, and cas7 (Figure 1A), making it 70 a minimal system24,25. A previously constructed Pseudomonas aeruginosa PAO1 strain (PAO1IC) 71 with inducible cas genes and crRNAs26 was used here to conduct targeted genome manipulation. 72 The expression of a crRNA targeting the genome caused a transient growth delay (Figure 1B), 73 but survivors were isolated after extended growth. By targeting phzM, a gene required for 74 production of a blue-green pigment (pyocyanin), we observed yellow cultures (Figure 1C) for 16 75 out of 36 (44%) biological replicates (18 recovered isolates from two independent phzM targeting 3 bioRxiv preprint doi: https://doi.org/10.1101/860999; this version posted December 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 76 crRNAs). PCR of genomic DNA confirmed that the yellow cultures had lost this region, while blue- 77 green survivors maintained it (Supplementary Figure 1). Three of these PAO1IC deletion strains 78 were sequenced, revealing deletions of 23.5 kb, 52.8 kb, and 60.1 kb, and each one was bi- 79 directional relative to the crRNA target site (Figure 1D). This demonstrated the potential for Type 80 I-C Cas3 systems to be used to induce large genomic deletions with random boundaries 81 surrounding a programmed target site. 82 To determine the in vivo processivity of the Cas3 enzyme, we targeted 2 of the 16 extended non- 83 essential (XNES) regions >100 kb in length (Supplementary Table 1) identified from a transposon 84 sequencing (TnSeq) data set27. The frequency of deletions generated by crRNAs targeting XNES 85 1 and XNES 2 (along with additional targeting of phzM, which is found in XNES 15) was quantified 86 revealing that 20-40 % of the surviving colonies had deletions (Figure 2A). To understand how 87 cells lacking large deletions had survived self-targeting, three possibilities were considered: i) a 88 cas gene mutation, ii) a PAM or protospacer mutation, or iii) a mutation to the plasmid expressing 89 the crRNA. Three non-deletion survivors from each of the six self-targeting crRNAs had functional 90 cas genes when the self-targeting crRNA was replaced with a phage targeting crRNA 91 (Supplementary Figure 2A), and target sequencing revealed no mutations. PCR-amplification and 92 sequencing of the crRNA-expressing plasmids isolated from the survivors revealed the primary 93 escape mechanism: recombination between the direct repeats, leading to the loss of the spacer 94 (Supplementary Figure 2B). The resulting bands from an additional 17 survivors that lacked 95 deletions were also ~60 bp shorter (Supplementary Figure 2C), consistent with the loss of one 96 repeat and spacer. 97 Spacer excision was successfully prevented by engineering a modified repeat (MR), with six 98 mutated nucleotides in the stem and three in the loop of the second repeat (Figure 2B), disrupting 99 homology between the two direct repeats. A phage-targeting crRNA with this new design targeted 100 phage as well or better than the same crRNA with unmodified repeats (Supplementary Figure 101 3A). Using the same self-targeting spacers designed against phzM, XNES 1, and XNES 2 with 102 the MR resulted in a robust increase in editing efficiencies to 94-100% for the six tested crRNAs 103 (Figure 2A) and spacer excision was no longer detected.
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