Roles of DNA helicases and Exo1 in the avoidance of mutations induced by Top1-mediated cleavage at ribonucleotides in DNA

Niu, Hengyao; Potenski, Catherine J.; Epshtein, Anastasiya; Sung, Patrick; Klein, Hannah L.

doi:10.1080/15384101.2015.1128594

Cited by 8 publications

(5 citation statements)

References 21 publications

(37 reference statements)

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“…A secondary Top1 cleavage less than six nucleotides from the initial Top1 cleavage site, followed by ligation across a 2-5 base pair gap, could account for these mutations. Since tdp1∆ and apn2 ∆ led to a modest increase of slippage mutation rate in rnh202∆ 14 , we examined the effect of APN2 gene deletion on Top1-induced mutagenesis in wild type and tdp1 deleted cells using the lys2 ΔA746(AG) 4 frameshift reversion assay, which detects 2- to 5-bp deletion events 4,13 (Figure 4D). The effect of APN1 deletion was also measured as a control.…”

Section: Resultsmentioning

confidence: 99%

“…Although Tdp1 doesn’t process the 2’, 3’ cyclic phosphate terminated end, it plays a role in the avoidance of slippage mutations, presumably through the removal of Top1-cc following the second Top1 cleavage ( 14 and Supplementary Figure 5). apn2∆ also led to an increased slippage mutation rate, which may be attributed to Apn2’s activity in Top1cc removal.…”

Section: Discussionmentioning

confidence: 99%

“…Top1 can also induce additional cleavage a few bases from the nick and form a Top1 cleavage complex (Top1cc) similar to that found in cells treated with the Top1 poison, camptothecin (CPT) 8,9,11 . At short repeat sequences, secondary Top1 cleavage and ligation may produce slippage type mutagenesis 4,13,14 . Unwinding and degradation of the 5’ nicks by Srs2 and Exo1 suppress Top1-mediated ligation across the gap and initiates an error-free repair 13 .…”

Section: Introductionmentioning

confidence: 99%

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Apn2 resolves blocked 3′ ends and suppresses Top1-induced mutagenesis at genomic rNMP sites

Wang

Seol

et al. 2019

Nat Struct Mol Biol

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Ribonucleotides (rNMPs) mis-incorporated during DNA replication are removed by RNase H2 dependent excision repair or by Topoisomerase I – catalyzed cleavage. Top1 cleavage of rNMPs produces 3’ ends harboring terminal adducts, such as 2’, 3’ cyclic phosphate or Top1 cleavage complex (Top1cc), and leads to frequent mutagenesis and DNA damage checkpoint induction. We surveyed a range of candidate enzymes from Saccharomyces cerevisiae for potential roles in Top1 dependent genomic rNMP removal. Genetic and biochemical analyses reveal that Apn2 resolves phosphotyrosine-DNA conjugates, terminal 2’, 3’ cyclic phosphates and their hydrolyzed products. APN2 also suppresses 2-bp slippage mutagenesis in RNH201 -deficient cells. Our results define additional activities of Apn2 in resolving a wide range of 3’- end blocks and identify a role of Apn2 in maintaining genome integrity during rNMP repair.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Apn2 resolves blocked 3′ ends and suppresses Top1-induced mutagenesis at genomic rNMP sites

Wang

Seol

et al. 2019

Nat Struct Mol Biol

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“…Thus, TDP1 contributes to genomic stability. Indeed, the loss of Tdp1 function affects mutation rates at repeat sequences in yeast 24 . These suggest that the reduced expression of TDP1 might contribute to genomic instability often seen in ATL cells.…”

Section: Discussionmentioning

confidence: 99%

HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia

Takiuchi¹,

Kobayashi²,

Tada³

et al. 2017

Sci Rep

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Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). We recently reported that abacavir, an anti-HIV-1 drug, potently and selectively kills ATL cells. This effect was attributed to the reduced expression of tyrosyl-DNA-phosphodiesterase 1 (TDP1), a DNA repair enzyme, in ATL cells. However, the molecular mechanism underlying the downregulation of TDP1 in ATL cells remains elusive. Here we identified the core promoter of the TDP1 gene, which contains a conserved nuclear respiratory factor 1 (NRF-1) binding site. Overexpression of NRF-1 increased TDP1-promoter activity, whereas the introduction of dominant-negative NRF-1 repressed such activity. Overexpression of NRF-1 also upregulated endogenous TDP-1 expression, while introduction of shNRF-1 suppressed TDP1 in Jurkat T cells, making them susceptible to abacavir. These results indicate that NRF-1 is a positive transcriptional regulator of TDP1-gene expression. Importantly, we revealed that HTLV-1 bZIP factor (HBZ) protein which is expressed in all ATL cases physically interacts with NRF-1 and inhibits the DNA-binding ability of NRF-1. Taken together, HBZ suppresses TDP1 expression by inhibiting NRF-1 function in ATL cells. The HBZ/NRF-1/TDP1 axis provides new therapeutic targets against ATL and might explain genomic instability leading to the pathogenesis of ATL.

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“…Removal of the 5’-OH precludes subsequent Top1-mediated ligation after the second cleavage, thereby preventing rNMP-dependent deletions. Finally, the Sgs1 3’>5’ helicase and the Tdp1 tyrosyl-DNA phosphodiesterase were identified in a candidate gene approach as additional activities that likely suppress ribonucleotide-dependent deletions [70]. Sgs1 may act similarly to Srs2, and Tdp1 presumably removes the Top1cc generated by the second cleavage event.…”

Section: Mechanism Of Top1-dependent Deletions At Ribonucleotidesmentioning

confidence: 99%

Ribonucleotides and Transcription-Associated Mutagenesis in Yeast

Cho

Jinks-Robertson

2017

Journal of Molecular Biology

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High levels of transcription stimulate mutation rates in microorganisms and this occurs primarily through an enhanced accumulation of DNA damage. The major source of transcription-associated damage in yeast is topoisomerase I (Top1), an enzyme that removes torsional stress that accumulates when DNA strands are separated. Top1 relieves torsional stress by nicking and re-sealing one DNA strand, and some Top1-dependent mutations are due to trapping and processing of the covalent cleavage intermediate. Most, however, reflect enzyme incision at ribonucleotides, which are the most abundant non-canonical component of DNA. In either case, Top1 generates a distinctive mutation signature comprised of short deletions in tandem repeats; in the specific case of ribonucleotide-initiated events, mutations reflect sequential cleavage by the enzyme. Top1-dependent mutations do not require highly activated transcription, but their levels are greatly increased by transcription, which partially reflects an interaction of Top1 with RNA polymerase. Recent studies have demonstrated that Top1-dependent mutations exhibit a strand bias, with the nature of the bias differing depending on the transcriptional status of the underlying DNA. Under low-transcription conditions, most Top1-dependent mutations arise in the context of replication and reflect incision at ribonucleotides incorporated during leading-strand synthesis. Under high-transcription conditions, most Top1-dependent events arise when the enzyme cleaves the non-transcribed strand of DNA. In addition to increasing genetic instability in growing cells, Top1 activity in transcriptionally active regions may be a source of mutations in quiescent cells.

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Roles of DNA helicases and Exo1 in the avoidance of mutations induced by Top1-mediated cleavage at ribonucleotides in DNA

Cited by 8 publications

References 21 publications

Apn2 resolves blocked 3′ ends and suppresses Top1-induced mutagenesis at genomic rNMP sites

Apn2 resolves blocked 3′ ends and suppresses Top1-induced mutagenesis at genomic rNMP sites

HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia

Ribonucleotides and Transcription-Associated Mutagenesis in Yeast

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