Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand

Teasley, Daniel C.; Parajuli, Shankar P.; Nguyen, Mai; Moore, Hayley R.; Alspach, Elise; Lock, Ying Jie; Honaker, Yuchi; Saharia, Abhishek; Piwnica‐Worms, Helen; Stewart, Sheila A.

doi:10.1074/jbc.m115.647388

Cited by 30 publications

(46 citation statements)

References 52 publications

(25 reference statements)

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“…Finally, our analysis identified RNASEH2A , FEN1 , and SSRP1 as miR-493-5p targets; these genes are known to be implicated in multiple genome-stabilizing pathways, including the degradation of transcriptionally generated R-loops (Herrera-Moyano et al, 2014; Teasley et al, 2015) and RER pathway. R-loops are an established source of genome instability and a potential driver of tumorigenesis (Aguilera and García-Muse, 2012; Aguilera and Gómez-González, 2017; Santos-Pereira and Aguilera, 2015; Sollier and Cimprich, 2015).…”

Section: Discussionmentioning

confidence: 92%

“…As stated above, top hits from our bioinformatics analysis identified targets for miR-493-5p like FEN1 , SSRP1 , and RNASEH2A that are known to play a role in R-loop processing and ribonucleotide excision repair (RER) pathway (Figure 5A; Herrera-Moyano et al, 2014; Teasley et al, 2015; Williams et al, 2016) To investigate the impact of miR-493-5p on R-loop processing, we used a monoclonal S9.6 antibody that specifically detects RNA-DNA hybrids. We measured S9.6 signal intensity in miR-493-5p-overexpressing BRCA2 -mutated VU423 cells and detected a significant increase in R-loops (Figure 5B), which was abolished upon transient overexpression of GFP-tagged RNaseH1.…”

Section: Resultsmentioning

confidence: 99%

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Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

et al. 2018

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SUMMARY BRCA1/2-mutated ovarian cancers (OCs) are defective in homologous recombination repair (HRR) of double-strand breaks (DSBs) and thereby sensitive to platinum and PARP inhibitors (PARPis). Multiple PARPis have recently received US Food and Drug Administration (FDA) approval for treatment of OCs, and resistance to PARPis is a major clinical problem. Utilizing primary and recurrent BRCA1/2-mutated carcinomas from OC patients, patient-derived lines, and an in vivo BRCA2-mutated mouse model, we identified a microRNA, miR-493-5p, that induced platinum/PARPi resistance exclusively in BRCA2-mutated carcinomas. However, in contrast to the most prevalent resistance mechanisms in BRCA mutant carcinomas, miR-493-5p did not restore HRR. Expression of miR-493-5p in BRCA2-mutated/depleted cells reduced levels of nucleases and other factors involved in maintaining genomic stability. This resulted in relatively stable replication forks, diminished single-strand annealing of DSBs, and increased R-loop formation. We conclude that impact of miR-493-5p on multiple pathways pertinent to genome stability cumulatively causes PARPi/platinum resistance in BRCA2 mutant carcinomas.

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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

et al. 2018

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“…Recently it has been shown that it plays a major role in telomere stabilization during replication, both at the leading, as well as the lagging strands [70]. At the lagging strand, FEN1 participates in replication fork progression, reinitiation and telomere stability [70]. At the leading strand, FEN1 cleaves the RNA:DNA hybrids that are generated during TERRA transcription.…”

Section: Telomere Fragility and Sister Chromatid Lossmentioning

confidence: 99%

“…At the leading strand, FEN1 cleaves the RNA:DNA hybrids that are generated during TERRA transcription. Removal of RNA fragments from the DNA as the replication progresses is important to limit telomere fragility and promote DNA repair at the leading strand [70]. Owing to its ability to stabilize telomeres, FEN1 may be important for telomere lengthening in ALT cells.…”

Section: Telomere Fragility and Sister Chromatid Lossmentioning

confidence: 99%

“…Owing to its ability to stabilize telomeres, FEN1 may be important for telomere lengthening in ALT cells. However, there is a controversy, since FEN1 inhibits TERRA RNA:DNA hybrid formation, and these hybrids are known to support recombination events in ALT [70]. Studies have revealed that depletion of FEN1 leads to sister chromatid loss in ALT telomeres.…”

Section: Telomere Fragility and Sister Chromatid Lossmentioning

confidence: 99%

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A transcriptome and literature guided algorithm for reconstruction of pathways to assess activity of telomere maintenance mechanisms

Nersisyan

Arakelyan

2017

Preprint

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Activation of telomere maintenance mechanisms (TMMs) is a crucial factor for indefinite proliferation of cancer cells. The most common TMM is based on the action of telomerase, but in some cancers telomeres are elongated via homologous recombination based alternative mechanism (ALT). Despite their importance, little is known about TMM regulation and factors responsible for TMM phenotype choice in different cells. Currently, many studies address the involvement of few genes in TMMs, but a consensus unified picture of the full process is missing.We have developed a computational biology framework combining knowledge-and data-driven approaches to aid in understanding of TMMs. It is based on a greedy algorithm with three core modules: (1) knowledge-based construction/modification of molecular pathways for telomerase-dependent and alternative TMMs, (2) coupled with gene expression data-based validation with an in-house pathway signal flow (PSF) algorithm, and (3) iteration of these two coupled steps until converging at pathway topologies that best reflect state of the art knowledge and are in maximum accordance with the data. We have used gene expression data derived from cell lines and tumor tissues and have performed extensive literature search and multiple cycles of greedy iterations until reaching TMM assessment accuracy of 100% and 77%, respectively.Availability of TMM pathways that best reflect recent knowledge and data will facilitate better understanding of TMM processes. As novel experimental findings in TMM biology emerge, and new datasets are generated, our approach may be used to further expand/improve the pathways, possibly allowing for making distinctions not only between telomerase-dependent and ALT TMMs, but also among their different subtypes. Moreover, this method may be used

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Challenging endings: How telomeres prevent fragility

Glousker

Lingner

2021

BioEssays

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It has become apparent that difficulties to replicate telomeres concern not only the very ends of eukaryotic chromosomes. The challenges already start when the replication fork enters the telomeric repeats. The obstacles encountered consist mainly of noncanonical nucleic acid structures that interfere with replication if not resolved.Replication stress at telomeres promotes the formation of so-called fragile telomeres displaying an abnormal appearance in metaphase chromosomes though their exact molecular nature remains to be elucidated. A substantial number of factors is required to counteract fragility. In this review we promote the hypothesis that telomere fragility is not caused directly by an initial insult during replication but it results as a secondary consequence of DNA repair of damaged replication forks by the homologous DNA recombination machinery. Incomplete DNA synthesis at repair sites or partial chromatin condensation may become apparent as telomere fragility. Fragility and DNA repair during telomere replication emerges as a common phenomenon which exacerbates in multiple disease conditions.

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Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand

Cited by 30 publications

References 52 publications

Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

A transcriptome and literature guided algorithm for reconstruction of pathways to assess activity of telomere maintenance mechanisms

Challenging endings: How telomeres prevent fragility

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