Homologous recombination and the repair of DNA double-strand breaks

Wright, William D.; Shah, Shanaya Shital; Heyer, Wolf Dietrich

doi:10.1074/jbc.tm118.000372

Cited by 533 publications

(480 citation statements)

References 113 publications

(136 reference statements)

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“…DNA recombination triggered by tandem paired nicking results in consequences analogous to those described in Holliday's model (Holliday, 1964;Liu and West, 2004). It is now widely accepted that DSBs promote homologous recombination (HR) (Chapman et al, 2012;Wright et al, 2018). Meanwhile, our study demonstrated that iso-positional nicking of two homologous DNA fragments promotes a type of recombination that is similar to HR.…”

Section: Discussionsupporting

confidence: 58%

Tandem paired nicking promotes precise genome editing with scarce interference by p53

Hyodo

Rahman

Karnan

et al. 2019

Preprint

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Targeted knock-in mediated by double-stranded DNA cleavage is accompanied by unwanted insertions and deletions (indels) at on-target and off-target sites.A nick-mediated approach scarcely generates indels but exhibits reduced efficiency of targeted knock-in. Here, we demonstrate that tandem paired nicking, a method for targeted knock-in involving two Cas9 nickases that create nicks at the homologous regions of the donor DNA and the genome in the same strand, scarcely creates indels at the edited genomic loci, while permitting the efficiency of targeted knock-in largely equivalent to that of the Cas9 nuclease-based approach. Tandem paired nicking seems to accomplish targeted knock-in via DNA recombination analogous to Holliday's model, and creates intended genetic changes in the genome without introducing additional nucleotide changes such as silent mutations. Targeted knock-in through tandem paired nicking neither triggers significant p53 activation nor occurs preferentially in p53-suppressed cells. These properties of tandem paired nicking demonstrate its utility in precision genome engineering.

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Section: Discussionsupporting

confidence: 58%

Tandem paired nicking promotes precise genome editing with scarce interference by p53

Hyodo

Rahman

Karnan

et al. 2019

Preprint

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“…The 3′ssDNA formed is first coated by RPA and then by the Rad51 recombinase forming a filament that will engage the search for a homologous sequence. This search, if successful, will be followed by the strand invasion of the template sequence, DNA polymerization and resolution of the D-loop structure to restore intact duplex DNA (Symington et al 2014;Wright et al 2018).…”

Section: Resection a Ticking Clock For Homology Search?mentioning

confidence: 99%

“…RPA, in turn, recruits proteins of the Rad52 epistasis group, such as Rad51, and these carry out strand invasion of the homologous template (Shinohara et al 1992;Sung 1994;Baumann et al 1996;Fortin and Symington 2002). New DNA synthesis copying the invaded duplex seals the DSB and after the resolution of the recombination intermediate structures, two intact DNA duplexes are restored (Symington et al 2014;Wright et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Keep moving and stay in a good shape to find your homologous recombination partner

Bordelet

Dubrana

2018

Curr Genet

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Genomic DNA is constantly exposed to damage. Among the lesion in DNA, double-strand breaks (DSB), because they disrupt the two strands of the DNA double helix, are the more dangerous. DSB are repaired through two evolutionary conserved mechanisms: Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Whereas NHEJ simply reseals the double helix with no or minimal processing, HR necessitates the formation of a 3′ssDNA through the processing of DSB ends by the resection machinery and relies on the recognition and pairing of this 3′ssDNA tails with an intact homologous sequence. Despite years of active research on HR, the manner by which the two homologous sequences find each other in the crowded nucleus, and how this modulates HR efficiency, only recently emerges. Here, we review recent advances in our understanding of the factors limiting the search of a homologous sequence during HR.

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“…In addition, MCM8-9 have been implicated in HR steps downstream of RAD51 loading 12,19 , including DNA damage-induced DNA synthesis at acutely stalled replication forks, presumably the sites of one-ended DSBs, and at I-SceIgenerated two-ended DSBs 19 . These observations raise the possibility that MCM8-9 can facilitate D-loop extension during recombination-associated DNA synthesis 19,20 .…”

Section: Main Textmentioning

confidence: 97%

Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

Huang

Taglialatela

Acharya

et al. 2019

Preprint

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Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. HR is carried out by a complex network of DNA repair factors. Here we identify C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a novel DNA repair factor involved in HR. MCM8IP-deficient cells exhibit HR defects, especially in long-tract gene conversion, occurring downstream of RAD51 loading, consistent with a role for MCM8IP in HR-dependent DNA synthesis. Moreover, loss of MCM8IP confers cellular sensitivity to crosslinking agents and PARP inhibition.Importantly, we identify a direct interaction with MCM8-9, a putative helicase complex mutated in Primary Ovarian Insufficiency, that is crucial for MCM8IP's ability to promote resistance to DNA damaging agents. In addition to its association with MCM8-9, MCM8IP also binds directly to RPA1. We show that the interactions of MCM8IP with both MCM8-9 and RPA are required to maintain replication fork progression in response to treatment with crosslinking agents. Collectively, our work identifies MCM8IP as a key regulator of DNA damage-associated DNA synthesis during DNA recombination and replication.

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Homologous recombination and the repair of DNA double-strand breaks

Cited by 533 publications

References 113 publications

Tandem paired nicking promotes precise genome editing with scarce interference by p53

Tandem paired nicking promotes precise genome editing with scarce interference by p53

Keep moving and stay in a good shape to find your homologous recombination partner

Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

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