Npl3, a new link between RNA-binding proteins and the maintenance of genome integrity

Santos-Pereira, José M.; Herrero, Ana B.; Moreno, Sergio; Aguilera, Andrés

doi:10.4161/cc.28708

Cited by 9 publications

(12 citation statements)

References 63 publications

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“…Deletion of either NPL3 or HPR1 is known to cause sensitivity to DNA damage (33). It has been proposed that these proteins promote genome stability through the proper formation of nuclear export-competent messenger ribonucleoprotein particles that promote the dissociation of mRNA from DNA and thereby prevent the collision of replication forks with R loops (33). Nuclear pore components may be targeted by DDR signaling to regulate this process or perhaps other functions.…”

Section: Discussionmentioning

confidence: 99%

Profiling DNA damage-induced phosphorylation in budding yeast reveals diverse signaling networks

Zhou

Elia

Naylor

et al. 2016

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

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The DNA damage response (DDR) is regulated by a protein kinase signaling cascade that orchestrates DNA repair and other processes. Identifying the substrate effectors of these kinases is critical for understanding the underlying physiology and mechanism of the response. We have used quantitative mass spectrometry to profile DDR-dependent phosphorylation in budding yeast and genetically explored the dependency of these phosphorylation events on the DDR kinases MEC1, RAD53, CHK1, and DUN1. Based on these screens, a database containing many novel DDR-regulated phosphorylation events has been established. Phosphorylation of many of these proteins has been validated by quantitative peptide phospho-immunoprecipitation and examined for functional relevance to the DDR through largescale analysis of sensitivity to DNA damage in yeast deletion strains. We reveal a link between DDR signaling and the metabolic pathways of inositol phosphate and phosphatidyl inositol synthesis, which are required for resistance to DNA damage. We also uncover links between the DDR and TOR signaling as well as translation regulation. Taken together, these data shed new light on the organization of DDR signaling in budding yeast.enomes of all organisms constantly experience life-threatening chemical and structural alterations because of the highly reactive chemical environments in which they reside and endogenous errors that occur during genome replication (1, 2). The ability to repair these lesions and maintain genomic stability is critical to organismal survival. A failure to maintain this stability leads to deleterious events such as mutagenesis, chromosomal rearrangements, gene amplifications or deletions, and the gain or loss of entire chromosomes. These events reduce the fitness and may even endanger the life of unicellular organisms while leading to developmental abnormalities and tumorigenesis in metazoans. Selective pressure from these DNA insults has resulted in the evolution of a higher-order regulatory pathway referred to as the DNA-damage response (DDR), which emerged to coordinate repair processes both by directing the types of repair to be used for particular lesions and by coordinating this repair with other cellular events such as cell-cycle progression (1).The eukaryotic DDR consists of two central protein kinases of the PIKK family, ataxia-telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) (3, 4). These proteins participate in sensing common intermediates in DNA repair, such as double-strand breaks or stalled replication forks, and thereupon phosphorylate downstream effectors to promote appropriate repair and cell-cycle coordination. The outlines of these pathways were originally established largely through studies in budding and fission yeast (1) and subsequently were expanded in mammals. In budding yeast, Tel1 (ATM homolog) and MEC1 (ATR homolog) carry out the bulk of the DNA-damage signaling. Unlike ATM in mammals, Tel1 has a relatively minor role in the budding yeast DDR (5). Downstream of these...

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Section: Discussionmentioning

confidence: 99%

Profiling DNA damage-induced phosphorylation in budding yeast reveals diverse signaling networks

Zhou

Elia

Naylor

et al. 2016

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

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“…In summary, Npl3 associates with telomeres in a TERRA‐ and R‐loop‐dependent manner. Based on Npl3's know function , we propose that it associates with nascent TERRA transcripts at telomeres (Fig H) as it does for other RNAP II transcripts . The depletion of Rat1 would then result in TERRA stabilization and allow Npl3 to persist in the vicinity of telomeres hence accounting for its increase ChIP signal (Fig E).…”

Section: Resultsmentioning

confidence: 94%

“…Samples were diluted in FA buffer supplemented with 0.1% sodium-deoxycholate (SOD). Chromatin extracts were separated by centrifugation (7 min at 17,949 g-force) and then sonicated in two rounds of 10 cycles (30 s on, 30…”

Section: Tap-chip Tap-rip and Dripmentioning

confidence: 99%

Npl3 stabilizes R‐loops at telomeres to prevent accelerated replicative senescence

et al. 2020

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Telomere shortening rates must be regulated to prevent premature replicative senescence. TERRA R‐loops become stabilized at critically short telomeres to promote their elongation through homology‐directed repair (HDR), thereby counteracting senescence onset. Using a non‐bias proteomic approach to detect telomere binding factors, we identified Npl3, an RNA‐binding protein previously implicated in multiple RNA biogenesis processes. Using chromatin immunoprecipitation and RNA immunoprecipitation, we demonstrate that Npl3 interacts with TERRA and telomeres. Furthermore, we show that Npl3 associates with telomeres in an R‐loop‐dependent manner, as changes in R‐loop levels, for example, at short telomeres, modulate the recruitment of Npl3 to chromosome ends. Through a series of genetic and biochemical approaches, we reveal that Npl3 binds to TERRA and stabilizes R‐loops at short telomeres, which in turn promotes HDR and prevents premature replicative senescence onset. This may have implications for diseases associated with excessive telomere shortening.

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“…CBC promotes the recruitment of Npl3 to the ribosomal protein genes. Like Yra1, Npl3 also participates in mRNA export by facilitating the formation of exportcompetent mature mRNP (21,(58)(59)(60)(61)(62). CBC has been previously shown to interact genetically and physically with Npl3 (21).…”

mentioning

confidence: 99%

Distinct Functions of the Cap-Binding Complex in Stimulation of Nuclear mRNA Export

Sen

Barman

Kaja

et al. 2019

Molecular and Cellular Biology

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Cap-binding complex (CBC) associates cotranscriptionally with the cap structure at the 5= end of nascent mRNA to protect it from exonucleolytic degradation. Here, we show that CBC promotes the targeting of an mRNA export adaptor, Yra1 (forming transcription export [TREX] complex with THO and Sub2), to the active genes and enhances mRNA export in Saccharomyces cerevisiae. Likewise, recruitment of Npl3 (an hnRNP involved in mRNA export via formation of export-competent ribonuclear protein complex [RNP]) to the active genes is facilitated by CBC. Thus, CBC enhances targeting of the export factors and promotes mRNA export. Such function of CBC is not mediated via THO and Sub2 of TREX, cleavage and polyadenylation factors, or Sus1 (that regulates mRNA export via transcription export 2 [TREX-2]). However, CBC promotes splicing of SUS1 mRNA and, consequently, Sus1 protein level and mRNA export via TREX-2. Collectively, our results support the hypothesis that CBC promotes recruitment of Yra1 and Npl3 to the active genes, independently of THO, Sub2, or cleavage and polyadenylation factors, and enhances mRNA export via TREX and RNP, respectively, in addition to its role in facilitating SUS1 mRNA splicing to increase mRNA export through TREX-2, revealing distinct stimulatory functions of CBC in mRNA export.

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Npl3, a new link between RNA-binding proteins and the maintenance of genome integrity

Cited by 9 publications

References 63 publications

Profiling DNA damage-induced phosphorylation in budding yeast reveals diverse signaling networks

Profiling DNA damage-induced phosphorylation in budding yeast reveals diverse signaling networks

Npl3 stabilizes R‐loops at telomeres to prevent accelerated replicative senescence

Distinct Functions of the Cap-Binding Complex in Stimulation of Nuclear mRNA Export

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