Repair of strand breaks by homologous recombination.

doi:10.1101/CSHPERSPECT.A012740

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Repair of strand breaks by homologous recombination.

Journal Article•DOI•

Repair of strand breaks by homologous recombination.

Maria Jasin¹, Rodney Rothstein²•Institutions (2)

Memorial Sloan Kettering Cancer Center¹, Columbia University Medical Center²

01 Nov 2013-Cold Spring Harbor Perspectives in Biology (Cold Spring Harb Perspect Biol)-Vol. 5, Iss: 11

TL;DR: The enzymology of the process is discussed, followed by studies on DSB repair in living cells, and a historical context for the current view of HR is provided and how DSBs are processed during HR as well as interactions with other D SB repair pathways are described.

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Abstract: In this review, we discuss the repair of DNA double-strand breaks (DSBs) using a homologous DNA sequence (i.e., homologous recombination [HR]), focusing mainly on yeast and mammals. We provide a historical context for the current view of HR and describe how DSBs are processed during HR as well as interactions with other DSB repair pathways. We discuss the enzymology of the process, followed by studies on DSB repair in living cells. Whenever possible, we cite both original articles and reviews to aid the reader for further studies.

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Journal Article•DOI•

Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors

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Andrew V. Anzalone¹, Luke W. Koblan¹, Luke W. Koblan², Luke W. Koblan³, David R. Liu³, David R. Liu¹, David R. Liu² - Show less +3 more•Institutions (3)

Broad Institute¹, Howard Hughes Medical Institute², Harvard University³

22 Jun 2020-Nature Biotechnology

TL;DR: This work analyzes key considerations when choosing genome editing agents and identifies opportunities for future improvements and applications in basic research and therapeutics.

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Abstract: The development of new CRISPR-Cas genome editing tools continues to drive major advances in the life sciences. Four classes of CRISPR-Cas-derived genome editing agents-nucleases, base editors, transposases/recombinases and prime editors-are currently available for modifying genomes in experimental systems. Some of these agents have also moved rapidly into the clinic. Each tool comes with its own capabilities and limitations, and major efforts have broadened their editing capabilities, expanded their targeting scope and improved editing specificity. We analyze key considerations when choosing genome editing agents and identify opportunities for future improvements and applications in basic research and therapeutics.

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1,068 citations

Journal Article•DOI•

Gene therapy returns to centre stage

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Luigi Naldini¹•Institutions (1)

Vita-Salute San Raffaele University¹

15 Oct 2015-Nature

TL;DR: Technology for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.

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Abstract: Recent clinical trials of gene therapy have shown remarkable therapeutic benefits and an excellent safety record. They provide evidence for the long-sought promise of gene therapy to deliver 'cures' for some otherwise terminal or severely disabling conditions. Behind these advances lie improved vector designs that enable the safe delivery of therapeutic genes to specific cells. Technologies for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.

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918 citations

Journal Article•DOI•

CRISPR-Cas guides the future of genetic engineering.

[...]

Gavin J. Knott¹, Jennifer A. Doudna•Institutions (1)

University of California, Berkeley¹

31 Aug 2018-Science

TL;DR: The basic mechanisms that set the CRISPR-Cas toolkit apart from other programmable gene-editing technologies are described, highlighting the diverse and naturally evolved systems now functionalized as biotechnologies.

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Abstract: The diversity, modularity, and efficacy of CRISPR-Cas systems are driving a biotechnological revolution. RNA-guided Cas enzymes have been adopted as tools to manipulate the genomes of cultured cells, animals, and plants, accelerating the pace of fundamental research and enabling clinical and agricultural breakthroughs. We describe the basic mechanisms that set the CRISPR-Cas toolkit apart from other programmable gene-editing technologies, highlighting the diverse and naturally evolved systems now functionalized as biotechnologies. We discuss the rapidly evolving landscape of CRISPR-Cas applications, from gene editing to transcriptional regulation, imaging, and diagnostics. Continuing functional dissection and an expanding landscape of applications position CRISPR-Cas tools at the cutting edge of nucleic acid manipulation that is rewriting biology.

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888 citations

Journal Article•DOI•

Homologous Recombination and Human Health: The Roles of BRCA1, BRCA2, and Associated Proteins

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Rohit Prakash¹, Yu Zhang¹, Weiran Feng¹, Maria Jasin¹•Institutions (1)

Memorial Sloan Kettering Cancer Center¹

01 Apr 2015-Cold Spring Harbor Perspectives in Biology

TL;DR: This review summarizes recent findings on BRCA1, BRCa2, and associated proteins involved in human disease with an emphasis on their molecular roles and interactions.

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Abstract: Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks in mammalian cells, the defining step of which is homologous strand exchange directed by the RAD51 protein. The physiological importance of HR is underscored by the observation of genomic instability in HR-deficient cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HR genes. The tumor suppressors BRCA1 and BRCA2, key players at different stages of HR, are frequently mutated in familial breast and ovarian cancers. Other HR proteins, including PALB2 and RAD51 paralogs, have also been identified as tumor suppressors. This review summarizes recent findings on BRCA1, BRCA2, and associated proteins involved in human disease with an emphasis on their molecular roles and interactions.

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608 citations

Cites background from "Repair of strand breaks by homologo..."

...More complex pathways involve Holliday junction resolution or dissolution (Jasin and Rothstein 2013; see also Bizard and Hickson 2014; Wyatt and West 2014)....
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Journal Article•DOI•

Recombination, Pairing, and Synapsis of Homologs during Meiosis

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Denise Zickler¹, Nancy Kleckner²•Institutions (2)

University of Paris-Sud¹, Harvard University²

01 Jun 2015-Cold Spring Harbor Perspectives in Biology

TL;DR: This review provides an overview of recombination-mediated processes in physical and functional linkage with meiotic axial chromosome structure, with interplay in both directions, before, during, and after formation and dissolution of the synaptonemal complex.

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Abstract: Recombination is a prominent feature of meiosis in which it plays an important role in increasing genetic diversity during inheritance. Additionally, in most organisms, recombination also plays mechanical roles in chromosomal processes, most notably to mediate pairing of homologous chromosomes during prophase and, ultimately, to ensure regular segregation of homologous chromosomes when they separate at the first meiotic division. Recombinational interactions are also subject to important spatial patterning at both early and late stages. Recombination-mediated processes occur in physical and functional linkage with meiotic axial chromosome structure, with interplay in both directions, before, during, and after formation and dissolution of the synaptonemal complex (SC), a highly conserved meiosis-specific structure that links homolog axes along their lengths. These diverse processes also are integrated with recombination-independent interactions between homologous chromosomes, nonhomology-based chromosome couplings/clusterings, and diverse types of chromosome movement. This review provides an overview of these diverse processes and their interrelationships.

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608 citations

Additional excerpts

...This situation would seem to contrast with the case for sister-directed mitotic DSB repair where the two DSB ends appear to remain together, at least for much of the process (reviewed in Jasin and Rothstein 2013)....
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Journal Article•DOI•

A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.

[...]

Martin Jinek¹, Krzysztof Chylinski², Krzysztof Chylinski³, Ines Fonfara³, Michael H. Hauer¹, Jennifer A. Doudna, Emmanuelle Charpentier³ - Show less +3 more•Institutions (3)

University of California, Berkeley¹, Max F. Perutz Laboratories², Umeå University³

17 Aug 2012-Science

TL;DR: This study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.

...read moreread less

Abstract: Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide bacteria and archaea with adaptive immunity against viruses and plasmids by using CRISPR RNAs (crRNAs) to guide the silencing of invading nucleic acids. We show here that in a subset of these systems, the mature crRNA that is base-paired to trans-activating crRNA (tracrRNA) forms a two-RNA structure that directs the CRISPR-associated protein Cas9 to introduce double-stranded (ds) breaks in target DNA. At sites complementary to the crRNA-guide sequence, the Cas9 HNH nuclease domain cleaves the complementary strand, whereas the Cas9 RuvC-like domain cleaves the noncomplementary strand. The dual-tracrRNA:crRNA, when engineered as a single RNA chimera, also directs sequence-specific Cas9 dsDNA cleavage. Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.

...read moreread less

12,865 citations

"Repair of strand breaks by homologo..." refers background in this paper

...Evidence that singlestrand nicks or gaps are likewise repaired by HR in mammalian cells comes not only from studies with drugs like camptothecin but also from the use of site-specific nickases, such as meganucleases (Davis and Maizels 2011), zinc finger nucleases (Kim et al. 2012; Ramirez et al. 2012; Wang et al. 2012), CRISPR/Cas9 (Cong et al. 2013; Mali et al. 2013), and corrupted Rag proteins (Lee et al. 2004)....
[...]
...2009; Moscou and Bogdanove 2009) and even more so recently by the discovery of an RNA-guided nuclease in bacterial adaptive immunity termed CRISPR/Cas9 (Gasiunas et al. 2012; Jinek et al. 2012)....
[...]
...Nuclease design was greatly facilitated by the discovery of the simple DNA recognition code of TAL effector proteins from pathogenic bacteria, which invade plants (Boch et al. 2009; Moscou and Bogdanove 2009) and even more so recently by the discovery of an RNA-guided nuclease in bacterial adaptive immunity termed CRISPR/Cas9 (Gasiunas et al. 2012; Jinek et al. 2012)....
[...]
...…DNA recognition code of TAL effector proteins from pathogenic bacteria, which invade plants (Boch et al. 2009; Moscou and Bogdanove 2009) and even more so recently by the discovery of an RNA-guided nuclease in bacterial adaptive immunity termed CRISPR/Cas9 (Gasiunas et al. 2012; Jinek et al. 2012)....
[...]

Journal Article•DOI•

Multiplex Genome Engineering Using CRISPR/Cas Systems

[...]

Le Cong¹, Le Cong², F. Ann Ran¹, F. Ann Ran², David M. Cox², David M. Cox¹, Shuailiang Lin², Shuailiang Lin³, Robert P. J. Barretto⁴, Naomi Habib², Patrick D. Hsu¹, Patrick D. Hsu², Xuebing Wu², Wenyan Jiang⁵, Luciano A. Marraffini⁵, Feng Zhang² - Show less +12 more•Institutions (5)

Harvard University¹, Massachusetts Institute of Technology², Tsinghua University³, Columbia University⁴, Rockefeller University⁵

15 Feb 2013-Science

TL;DR: The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage as discussed by the authors.

...read moreread less

Abstract: Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.

...read moreread less

12,265 citations

Multiplex Genome Engineering Using CRISPR/Cas Systems

[...]

Le Cong, F. A. Ran, David Benjamin Turitz Cox, Shuailiang Lin, Robert P. J. Barretto, Naomi Habib, Patrick D. Hsu, Xuebing Wu, Wenyan Jiang, Luciano A. Marraffini, Feng Zhang - Show less +7 more

01 Feb 2013

TL;DR: Two different type II CRISPR/Cas systems are engineered and it is demonstrated that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.

...read moreread less

Abstract: Genome Editing Clustered regularly interspaced short palindromic repeats (CRISPR) function as part of an adaptive immune system in a range of prokaryotes: Invading phage and plasmid DNA is targeted for cleavage by complementary CRISPR RNAs (crRNAs) bound to a CRISPR-associated endonuclease (see the Perspective by van der Oost). Cong et al. (p. 819, published online 3 January) and Mali et al. (p. 823, published online 3 January) adapted this defense system to function as a genome editing tool in eukaryotic cells. A bacterial genome defense system is adapted to function as a genome-editing tool in mammalian cells. [Also see Perspective by van der Oost] Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.

...read moreread less

10,746 citations

"Repair of strand breaks by homologo..." refers background in this paper

...…drugs like camptothecin but also from the use of site-specific nickases, such as meganucleases (Davis and Maizels 2011), zinc finger nucleases (Kim et al. 2012; Ramirez et al. 2012; Wang et al. 2012), CRISPR/Cas9 (Cong et al. 2013; Mali et al. 2013), and corrupted Rag proteins (Lee et al. 2004)....
[...]
...Evidence that singlestrand nicks or gaps are likewise repaired by HR in mammalian cells comes not only from studies with drugs like camptothecin but also from the use of site-specific nickases, such as meganucleases (Davis and Maizels 2011), zinc finger nucleases (Kim et al. 2012; Ramirez et al. 2012; Wang et al. 2012), CRISPR/Cas9 (Cong et al. 2013; Mali et al. 2013), and corrupted Rag proteins (Lee et al. 2004)....
[...]
...Nuclease design was greatly facilitated by the discovery of the simple DNA recognition code of TAL effector proteins from pathogenic bacteria, which invade plants (Boch et al. 2009; Moscou and Bogdanove 2009) and even more so recently by the discovery of an RNA-guided nuclease in bacterial adaptive immunity termed CRISPR/Cas9 (Gasiunas et al. 2012; Jinek et al. 2012)....
[...]

Journal Article•DOI•

RNA-Guided Human Genome Engineering via Cas9

[...]

Prashant Mali¹, Luhan Yang¹, Kevin M. Esvelt², John Aach¹, Marc Güell¹, James E. DiCarlo³, Julie E. Norville¹, George M. Church¹, George M. Church² - Show less +5 more•Institutions (3)

Harvard University¹, Wyss Institute for Biologically Inspired Engineering², Boston University³

15 Feb 2013-Science

TL;DR: The type II bacterial CRISPR system is engineer to function with custom guide RNA (gRNA) in human cells to establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.

...read moreread less

Abstract: Bacteria and archaea have evolved adaptive immune defenses, termed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems, that use short RNA to direct degradation of foreign nucleic acids. Here, we engineer the type II bacterial CRISPR system to function with custom guide RNA (gRNA) in human cells. For the endogenous AAVS1 locus, we obtained targeting rates of 10 to 25% in 293T cells, 13 to 8% in K562 cells, and 2 to 4% in induced pluripotent stem cells. We show that this process relies on CRISPR components; is sequence-specific; and, upon simultaneous introduction of multiple gRNAs, can effect multiplex editing of target loci. We also compute a genome-wide resource of ~190 K unique gRNAs targeting ~40.5% of human exons. Our results establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.

...read moreread less

8,197 citations

"Repair of strand breaks by homologo..." refers background in this paper

...…drugs like camptothecin but also from the use of site-specific nickases, such as meganucleases (Davis and Maizels 2011), zinc finger nucleases (Kim et al. 2012; Ramirez et al. 2012; Wang et al. 2012), CRISPR/Cas9 (Cong et al. 2013; Mali et al. 2013), and corrupted Rag proteins (Lee et al. 2004)....
[...]
...Evidence that singlestrand nicks or gaps are likewise repaired by HR in mammalian cells comes not only from studies with drugs like camptothecin but also from the use of site-specific nickases, such as meganucleases (Davis and Maizels 2011), zinc finger nucleases (Kim et al. 2012; Ramirez et al. 2012; Wang et al. 2012), CRISPR/Cas9 (Cong et al. 2013; Mali et al. 2013), and corrupted Rag proteins (Lee et al. 2004)....
[...]
...Nuclease design was greatly facilitated by the discovery of the simple DNA recognition code of TAL effector proteins from pathogenic bacteria, which invade plants (Boch et al. 2009; Moscou and Bogdanove 2009) and even more so recently by the discovery of an RNA-guided nuclease in bacterial adaptive immunity termed CRISPR/Cas9 (Gasiunas et al. 2012; Jinek et al. 2012)....
[...]
...2012), CRISPR/Cas9 (Cong et al. 2013; Mali et al. 2013), and corrupted Rag proteins (Lee et al....
[...]

Journal Article•DOI•

Efficient genome editing in zebrafish using a CRISPR-Cas system

[...]

Woong Y. Hwang¹, Yanfang Fu¹, Deepak Reyon¹, Morgan L. Maeder¹, Shengdar Q. Tsai¹, Jeffry D. Sander¹, Randall T. Peterson¹, Randall T. Peterson², Jing-Ruey J. Yeh¹, J. Keith Joung¹ - Show less +6 more•Institutions (2)

Harvard University¹, Broad Institute²

01 Mar 2013-Nature Biotechnology

TL;DR: It is shown that the CRISPR-Cas system functions in vivo to induce targeted genetic modifications in zebrafish embryos with efficiencies similar to those obtained using zinc finger nucleases and transcription activator-like effector nucleases.

...read moreread less

Abstract: In bacteria, foreign nucleic acids are silenced by clustered, regularly interspaced, short palindromic repeats (CRISPR)--CRISPR-associated (Cas) systems. Bacterial type II CRISPR systems have been adapted to create guide RNAs that direct site-specific DNA cleavage by the Cas9 endonuclease in cultured cells. Here we show that the CRISPR-Cas system functions in vivo to induce targeted genetic modifications in zebrafish embryos with efficiencies similar to those obtained using zinc finger nucleases and transcription activator-like effector nucleases.

...read moreread less

2,897 citations

"Repair of strand breaks by homologo..." refers background in this paper

...These “designer” nucleases are being used for genome engineering in a variety of organisms in addition to mammalian cells, including zebrafish (Hwang et al. 2013) and livestock (Carlson et al. 2012)....
[...]
...These “designer” nucleases are being used for genome engineering in a variety of organisms in addition to mammalian cells, including zebrafish (Hwang et al. 2013) and livestock (Carlson et al....
[...]