Noncanonical views of homology-directed DNA repair

Verma, Priyanka; Greenberg, Roger A.

doi:10.1101/gad.280545.116

Cited by 117 publications

(92 citation statements)

References 223 publications

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“…4f). We speculate that related processes are invoked at other vulnerable regions of the genome 29–33 . The unique characteristics that differentiate this mechanism from scheduled S-phase replication may facilitate a better understanding of how alternative repair mechanisms enable genome evolution and enhance cancer cell fitness.…”

Section: Discussionmentioning

confidence: 94%

Break-induced telomere synthesis underlies alternative telomere maintenance

Dilley

Verma

Cho

et al. 2016

Nature

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353

425

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Homology-directed DNA repair is essential for genome maintenance through templated DNA synthesis. Alternative lengthening of telomeres (ALT) necessitates homology-directed DNA repair to maintain telomeres in about 10–15% of human cancers. How DNA damage induces assembly and execution of a DNA replication complex (break-induced replisome) at telomeres or elsewhere in the mammalian genome is poorly understood. Here we define break-induced telomere synthesis and demonstrate that it utilizes a specialized replisome, which underlies ALT telomere maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. Proliferating cell nuclear antigen (PCNA) loading by replication factor C (RFC) acts as the initial sensor of telomere damage to establish predominance of DNA polymerase δ (Pol δ) through its POLD3 subunit. Break-induced telomere synthesis requires the RFC–PCNA–Pol δ axis, but is independent of other canonical replisome components, ATM and ATR, or the homologous recombination protein Rad51. Thus, the inception of telomere damage recognition by the break-induced replisome orchestrates homology-directed telomere maintenance.

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Section: Discussionmentioning

confidence: 94%

Break-induced telomere synthesis underlies alternative telomere maintenance

Dilley

Verma

Cho

et al. 2016

Nature

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353

425

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“…A number of ‘alternative’ HDR pathways do not involve RAD51-mediated strand invasion [reviewed by (86)], among them HDR supported by SSO donors. At nicks, HDR by SSO donors requires RPA, but is stimulated dramatically (10-fold or more) upon depletion of RAD51 itself or factors that promote loading of RAD51 on DNA, including BRCA2 and its binding partners PALB2 and SHFM1; or by expression of the dominant negative RAD51K133R mutant or the inhibitory BRC3 peptide (9,10,87).…”

Section: Discussionmentioning

confidence: 99%

Initiation of homologous recombination at DNA nicks

Maizels

Davis

2018

Nucleic Acids Research

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Discontinuities in only a single strand of the DNA duplex occur frequently, as a result of DNA damage or as intermediates in essential nuclear processes and DNA repair. Nicks are the simplest of these lesions: they carry clean ends bearing 3′-hydroxyl groups that can undergo ligation or prime new DNA synthesis. In contrast, single-strand breaks also interrupt only one DNA strand, but they carry damaged ends that require clean-up before subsequent steps in repair. Despite their apparent simplicity, nicks can have significant consequences for genome stability. The availability of enzymes that can introduce a nick almost anywhere in a large genome now makes it possible to systematically analyze repair of nicks. Recent experiments demonstrate that nicks can initiate recombination via pathways distinct from those active at double-strand breaks (DSBs). Recombination at targeted DNA nicks can be very efficient, and because nicks are intrinsically less mutagenic than DSBs, nick-initiated gene correction is useful for genome engineering and gene therapy. This review revisits some physiological examples of recombination at nicks, and outlines experiments that have demonstrated that nicks initiate homology-directed repair by distinctive pathways, emphasizing research that has contributed to our current mechanistic understanding of recombination at nicks in mammalian cells.

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“…It remains unclear how JMs are formed in the absence of Rad51 or Rad54 in centromeres. However, homology-mediated recombination that occurs independently of Rad51 and Rad54 has been reported, such as single-strand annealing (SSA) and microhomology-mediated end joining (MMEJ) (for review, see (72,73)) (Figure 7A). A set of proteins including Rad59, Rdh54 and Rad50 have been implicated in the Rad51-independent pathway of DSB repair in budding yeast (74).…”

Section: Discussionmentioning

confidence: 99%

Rad51 and Rad54 promote noncrossover recombination between centromere repeats on the same chromatid to prevent isochromosome formation

Onaka¹,

Toyofuku²,

Inoue³

et al. 2016

Nucleic Acids Res

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Centromeres consist of DNA repeats in many eukaryotes. Non-allelic homologous recombination (HR) between them can result in gross chromosomal rearrangements (GCRs). In fission yeast, Rad51 suppresses isochromosome formation that occurs between inverted repeats in the centromere. However, how the HR enzyme prevents homology-mediated GCRs remains unclear. Here, we provide evidence that Rad51 with the aid of the Swi/Snf-type motor protein Rad54 promotes non-crossover recombination between centromere repeats to prevent isochromosome formation. Mutations in Rad51 and Rad54 epistatically increased the rates of isochromosome formation and chromosome loss. In sharp contrast, these mutations decreased gene conversion between inverted repeats in the centromere. Remarkably, analysis of recombinant DNAs revealed that rad51 and rad54 increase the proportion of crossovers. In the absence of Rad51, deletion of the structure-specific endonuclease Mus81 decreased both crossovers and isochromosomes, while the cdc27/pol32-D1 mutation, which impairs break-induced replication, did not. We propose that Rad51 and Rad54 promote non-crossover recombination between centromere repeats on the same chromatid, thereby suppressing crossover between non-allelic repeats on sister chromatids that leads to chromosomal rearrangements. Furthermore, we found that Rad51 and Rad54 are required for gene silencing in centromeres, suggesting that HR also plays a role in the structure and function of centromeres.

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Noncanonical views of homology-directed DNA repair

Cited by 117 publications

References 223 publications

Break-induced telomere synthesis underlies alternative telomere maintenance

Break-induced telomere synthesis underlies alternative telomere maintenance

Initiation of homologous recombination at DNA nicks

Rad51 and Rad54 promote noncrossover recombination between centromere repeats on the same chromatid to prevent isochromosome formation

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