Hypermutability of Damaged Single-Strand DNA Formed at Double-Strand Breaks and Uncapped Telomeres in Yeast Saccharomyces cerevisiae

Yang, Yong; Sterling, Joan F.; Storici, Francesca; Resnick, Michael A.; Gordenin, Dmitry A.

doi:10.1371/journal.pgen.1000264

Cited by 134 publications

(211 citation statements)

References 43 publications

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“…A connection between stalled replication forks and DSBs in yeast also has been observed for CTG repeats (22) and in mec1 cells treated with hydroxyurea (27). The recombinogenic repair of DSBs is known to be error prone (28), and single-stranded DNA recombination intermediates are particularly susceptible to mutations (29). We believe, therefore, that error-prone DSB repair might be responsible for RIM.…”

Section: Discussionmentioning

confidence: 55%

Genome rearrangements caused by interstitial telomeric sequences in yeast

Aksenova

Greenwell

Dominska

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

106

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Significance Telomeres are composed of simple repetitive DNA sequences that normally are located at the ends of the chromosomes. Occasionally, however, they also are found inside chromosomes. Some of these internal or interstitial telomeric sequences colocalize with chromosomal fragile sites, preferred sites of breakage in some cancers and hereditary human diseases. The mechanisms responsible for genome instability at interstitial telomeric sequences are unclear. We developed a system to study genetic instabilities caused by these sequences in a model organism (baker’s yeast) that allowed us to characterize various chromosomal rearrangements and to measure the likelihood of their formation. We found that interstitial telomeric sequences promote the formation of deletions, duplications, inversions, and translocations, and we proposed molecular mechanisms responsible for these events.

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Section: Discussionmentioning

confidence: 55%

Genome rearrangements caused by interstitial telomeric sequences in yeast

Aksenova

Greenwell

Dominska

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

106

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“…If unrepaired, they can lead to DSBs during subsequent replication. In addition, ssDNA is more susceptible to mutagens because there is no complementary strand to template the correction of lesions (38). Here, we show that the combined three systems available in most eukaryotes to provide toleration of bulky lesions-NER, TLS, and HR-prevent and repair ssDNA that can arise in G2 cells.…”

Section: Compromised Tls Activity Leads To Increased Recombinant Molementioning

confidence: 79%

Homologous recombination rescues ssDNA gaps generated by nucleotide excision repair and reduced translesion DNA synthesis in yeast G2 cells

Westmoreland

Resnick

2013

Proc. Natl. Acad. Sci. U.S.A.

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Repair of DNA bulky lesions often involves multiple repair pathways such as nucleotide-excision repair, translesion DNA synthesis (TLS), and homologous recombination (HR). Although there is considerable information about individual pathways, little is known about the complex interactions or extent to which damage in single strands, such as the damage generated by UV, can result in double-strand breaks (DSBs) and/or generate HR. We investigated the consequences of UV-induced lesions in nonreplicating G2 cells of budding yeast. In contrast to WT cells, there was a dramatic increase in ssDNA gaps for cells deficient in the TLS polymerases η (Rad30) and ζ (Rev3). Surprisingly, repair in TLS-deficient G2 cells required HR repair genes RAD51 and RAD52, directly revealing a redundancy of TLS and HR functions in repair of ssDNAs. Using a physical assay that detects recombination between circular sister chromatids within a few hours after UV, we show an approximate three-fold increase in recombinants in the TLS mutants over that in WT cells. The recombination, which required RAD51 and RAD52, does not appear to be caused by DSBs, because a dose of ionizing radiation producing 20 times more DSBs was much less efficient than UV in producing recombinants. Thus, in addition to revealing TLS and HR functional redundancy, we establish that UV-induced recombination in TLS mutants is not attributable to DSBs. These findings suggest that ssDNA that might originate during the repair of closely opposed lesions or of ssDNA-containing lesions or from uncoupled replication may drive recombination directly in various species, including humans.

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“…HR repairs gaps with high fidelity using the sister chromatid as a template. However, DSB repair by HR is not error free and is associated with mutagenesis (Strathern et al 1995;Yang et al 2008;Malkova and Haber 2012). Pathway choice between translesion DNA synthesis, template switch by fork regression or HR appears to be controlled by several pathways.…”

Section: Dsb-repair Pathway Choice or How Resection Commits To Hrmentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

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Hypermutability of Damaged Single-Strand DNA Formed at Double-Strand Breaks and Uncapped Telomeres in Yeast Saccharomyces cerevisiae

Cited by 134 publications

References 43 publications

Genome rearrangements caused by interstitial telomeric sequences in yeast

Genome rearrangements caused by interstitial telomeric sequences in yeast

Homologous recombination rescues ssDNA gaps generated by nucleotide excision repair and reduced translesion DNA synthesis in yeast G2 cells

Regulation of Recombination and Genomic Maintenance

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