Targeted Formation of 8-Oxoguanine in Telomeres

Barnes, Ryan; Thosar, Sanjana A; Fouquerel, Elise; Opresko, Patricia L.

doi:10.1007/978-1-0716-2063-2_9

Cited by 4 publications

(7 citation statements)

References 13 publications

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“…Surprisingly, relative cell counts 4 days after 20 min of DL exposure showed a partial rescue of 8oxoG-induced growth reduction in single KO cells, and a near complete rescue in DKO cells, while all cell lines were unaffected by dye or light alone (Figure 1C). Increasing the DL exposure from 5 to 20 min amplified the differential response of glycosylase deficient and WT cells to telomeric damage (Figure S1A), consistent with greater 8oxoG production with longer exposures 33 . Simultaneous treatment with 20 min DL and the OGG1 inhibitor TH5487 (OGG1i), which prevents OGG1 binding 35 , also partially rescued the cell growth reduction in WT cells, similar to OGG1 KO, whereas a close structural analog (OGG1i NA ) had no effect (Figure S1B).…”

Section: Resultsmentioning

confidence: 54%

“…To study how oxidative damage impacts telomere function, we use a chemoptogenetic tool that generates 8oxoG by directing localized production of highly reactive singlet oxygen ( 1 O2) at telomeres 15 . Photosensitizer di-iodinated malachite green (MG2I) dye (D) produces 1 O2 when bound to a fluorogen activating peptide (FAP) fused with telomeric protein TRF1, and then activated with 660 nm light (L) 33,34 . We previously demonstrated that acute production of telomeric 8oxoG in non-diseased human BJ hTERT fibroblasts (BJ FAP-TRF1) increased senescent cells just 4 days after dye and light (DL) exposure 16 .…”

Section: Resultsmentioning

confidence: 99%

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OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence

Rosa

Barnes

Nyalapatla

et al. 2023

Preprint

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SUMMARYTelomeres are prone to formation of the common oxidative lesion 8-oxoguanine (8oxoG), and the acute production of 8oxoG damage at telomeres is sufficient to drive rapid cellular senescence. OGG1 and MUTYH glycosylases initiate base excision repair (BER) at 8oxoG sites to remove the lesion or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced senescence, and loss of both glycosylases results in a near complete rescue. Loss of these glycosylases also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that single-stranded break (SSB) intermediates arising downstream of glycosylase activity impair telomere replication. The failure to initiate BER in glycosylase-deficient cells suppresses PARylation at SSB intermediates and confers resistance to the synergistic effects of PARP inhibitors on damage-induced senescence. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which impair telomere replication and stability.

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Section: Resultsmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence

Rosa

Barnes

Nyalapatla

et al. 2023

Preprint

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“…To ensure that the increased sensitivity of U2OS FAP cells was not due to greater amounts of induced damage, we conducted the 8oxoG detection assay, in which FPG glycosylase and S1 nuclease convert 8oxoG lesions to DSBs in telomere restriction fragments. 53 Since both cell lines showed comparable amounts of cleaved telomere fragments after dye and light exposure in this assay ( Figures S3A and S3B ), we concluded that 8oxoG is more likely to induce replication stress at ALT telomeres compared to telomeres in Tel+ cancer cells.…”

Section: Resultsmentioning

confidence: 67%

“… 26 While 8oxoG imparts little to no distortion of the DNA helix and is far less disruptive to chromosome structure than a DSB, it is an abundant source of endogenous DNA damage, especially in telomeric sequences. 40 To examine whether oxidative damage impacts ALT-HDR, we used the FAP-TRF1 system to specifically generate 8oxoG at telomeres 53 and assayed for hallmarks of ALT activity. For this, we generated ALT+ cell lines that stably express FAP-mCerulean-TRF1 (termed FAP cells).…”

Section: Resultsmentioning

confidence: 99%

Oxidative guanine base damage plays a dual role in regulating productive ALT-associated homology-directed repair

Thosar,

Barnes,

Detwiler

et al. 2024

Cell Reports

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“…[33] Absence of sufficient telomere bases at chromosome ends in the cells defective in ATM protein can cause the chromosomes to fuse and result in dicentrics and complex chromosomal translocations. On the other hand, it has been demonstrated that oxidative stress reportedly accelerates telomere attrition [43][44][45][46] by inhibiting telomerase and disrupting the recognition by telomere-binding proteins which contributes to telomere uncapping. [43,46,47] This substantiates that telomeric DNA may be hypersensitive to oxidative DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Damage Induced Telomere Mediated Genomic Instability in Cells from Ataxia Telangiectasia Patients

Srikanth

Chowdhury²,

Low

et al. 2022

Genome Integr

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Our cellular genome is susceptible to cytotoxic lesions which include single strand breaks and double strand breaks among other lesions. Ataxia telangiectasia mutated (ATM) protein was one of the first DNA damage sensor proteins to be discovered as being involved in DNA repair and as well as in telomere maintenance. Telomeres help maintain the stability of our chromosomes by protecting the ends from degradation. Cells from ataxia telangiectasia (AT) patients lack ATM and accumulate chromosomal alterations. AT patients display heightened susceptibility to cancer. In this study, cells from AT patients (called as AT-/- and AT+/- cells) were characterized for genome stability status and it was observed that AT-/- cells show considerable telomere attrition. Furthermore, DNA damage and genomic instability were compared between normal (AT+/+ cells) and AT-/- cells exhibiting increased frequencies of spontaneous DNA damage and genomic instability markers. Both AT-/- and AT+/- cells were sensitive to sodium arsenite (1.5 and 3.0 μg/ml) and ionizing radiation-induced (2 Gy, gamma rays) oxidative stress. Interestingly, telomeric fragments were detected in the comet tails as revealed by comet-fluorescence in situ hybridization analysis, suggestive of telomeric instability in AT-/- cells upon exposure to sodium arsenite or radiation. Besides, there was an increase in the number of chromosome alterations in AT-/- cells following arsenite treatment or irradiation. In addition, complex chromosome aberrations were detected by multicolor fluorescence in situ hybridization in AT-/- cells in comparison to AT+/- and normal cells. Telomere attrition and chromosome alterations were detected even at lower doses of sodium arsenite. Peptide nucleic acid – FISH analysis revealed defective chromosome segregation in cells lacking ATM proteins. The data obtained in this study substantiates the role of ATM in telomere stability under oxidative stress.

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Targeted Formation of 8-Oxoguanine in Telomeres

Cited by 4 publications

References 13 publications

OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence

OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence

Oxidative guanine base damage plays a dual role in regulating productive ALT-associated homology-directed repair

Oxidative Damage Induced Telomere Mediated Genomic Instability in Cells from Ataxia Telangiectasia Patients

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