The Genetic Landscape of a Cell

Costanzo, Michael; Baryshnikova, Anastasia; Bellay, Jeremy; Kim, Yungil; Spear, Eric D.; Sevier, Carolyn S.; Ding, Huiming; Koh, Judice L.Y.; Toufighi, Kiana; Mostafavi, Sara; Prinz, Jeany; St.Onge, Robert P.; VanderSluis, Benjamin; Makhnevych, Taras; Vizeacoumar, Franco J.; Alizadeh, Solmaz; Bahr, Sondra; Brost, Renée L.; Chen, Yiqun; Çokol, Murat; Deshpande, Raamesh; Z, Li; Lin, Zhen Yuan; Liang, Wendy; Marback, Michaela; Paw, Jadine; Luis, Bryan Joseph San; Shuteriqi, Ermira; Tong, Amy; Dyk, Nydia Van; Wallace, Iain; Whitney, Joseph; Weirauch, Matthew T.; Zhong, Guoqing; Zhu, Hongwei; Houry, Walid; Brudno, Michael; Ragibizadeh, Sasan; Papp, Balázs; Pál, Csaba; Roth, Frederick P.; Giaever, Guri; Nislow, Corey; Troyanskaya, Olga G.; Bussey, Howard; Bader, Gary D.; Gingras, Anne‐Claude; Morris, Quaid; Kim, Philip M.; Kaiser, Chris A.; Myers, Chad L.; Andrews, Brenda; Boone, Charles

doi:10.1126/science.1180823

Cited by 2,000 publications

(2,878 citation statements)

References 36 publications

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“…complex [29][30][31][32][33][34][35] . Indeed, disruption of kinesin-14 alone or in combination with Lrs4 deletion, decreased subtelomeric DSB survival to levels similar to those seen in cells deficient in cohibin or Nup84 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process

et al. 2015

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DNA double-strand breaks (DSBs) are often targeted to nuclear pore complexes (NPCs) for repair. How targeting is achieved and the DNA repair pathways involved in this process remain unclear. Here, we show that the kinesin-14 motor protein complex (Cik1-Kar3) cooperates with chromatin remodellers to mediate interactions between subtelomeric DSBs and the Nup84 nuclear pore complex to ensure cell survival via break-induced replication (BIR), an error-prone DNA repair process. Insertion of a DNA zip code near the subtelomeric DSB site artificially targets it to NPCs hyperactivating this repair mechanism. Kinesin-14 and Nup84 mediate BIR-dependent repair at non-telomeric DSBs whereas perinuclear telomere tethers are only required for telomeric BIR. Furthermore, kinesin-14 plays a critical role in telomerase-independent telomere maintenance. Thus, we uncover roles for kinesin and NPCs in DNA repair by BIR and reveal that perinuclear telomere anchors license subtelomeric DSBs for this error-prone DNA repair mechanism.

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Section: Resultsmentioning

confidence: 99%

Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process

et al. 2015

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“…The interaction of Sds23 with the multi-drug transporters is particularly interesting, since such transporters might be able to pump caffeine out of cells. In contrast to the Sds23 interactome, no physical interactions with plasma membrane transporters have yet been identified for Sds24, although Costanzo et al (2010) did report genetic interactions between SDS24 and the genes that encode an S -adenosylmethionine permease, Sam3 (Rouillon et al, 1999), and a putative amino acid transporter, Avt5 (SGD Project, 2010).…”

Section: The Caffeine Suppressor Gene Interaction Networkmentioning

confidence: 99%

Identification of phosphatase 2A‐like Sit4‐mediated signalling and ubiquitin‐dependent protein sorting as modulators of caffeine sensitivity in S. cerevisiae

Hood-DeGrenier¹

2010

Yeast

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Caffeine exerts pleiotropic effects on eukaryotic cells via its ability to act as a lowaffinity adenosine analogue. Here we report that the genes HSE1, RTS3, SDS23 and SDS24 confer caffeine resistance when overexpressed in S. cerevisiae. The Hse1 protein functions in ubiquitin-dependent vacuolar protein sorting, whereas the other proteins are poorly characterized. Bioinformatic analysis of genetic and physical interaction data linked Rts3 and Sds23/24 to the phosphatase 2A-like Sit4 pathway. Combinatorial deletions of the identified suppressor genes conferred varying levels of caffeine hypersensitivity. For hse1 and rts3 mutants, caffeine sensitivity was partially rescued by sorbitol osmostabilization, suggesting possible cell wall integrity defects in these strains. Rapamycin sensitivity experiments linked the caffeine sensitivity of rts3 , but not that of sds23/24 or hse1 strains, to inhibition of the TORC1 kinase complex, a central regulator of cell growth and a known caffeine target. Epistasis experiments support a model in which Rts3 and Sds23/24 act in parallel to negatively regulate Sit4, while Hse1 confers caffeine resistance via a separate pathway. In summary, this study identifies the Sit4 phosphatase pathway and membrane protein dynamics as key modulators of caffeine-mediated inhibition of yeast cell growth and proposes novel functions for Rts3 and Sds23/24.

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“…To evaluate the 2-TF regulatory interactions, we downloaded the SGA genetic interaction dataset [25], which is composed of 1,711 queries crossed to 3,885 array strains. Of the 1,711 queries, 1,377 are deletion mutants of non-essential genes and 334 are essential gene alleles.…”

Section: Resultsmentioning

confidence: 99%

Inferring transcription factor collaborations in gene regulatory networks

Awad

Chen

2014

BMC Syst Biol

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BackgroundLiving cells are realized by complex gene expression programs that are moderated by regulatory proteins called transcription factors (TFs). The TFs control the differential expression of target genes in the context of transcriptional regulatory networks (TRNs), either individually or in groups. Deciphering the mechanisms of how the TFs control the expression of target genes is a challenging task, especially when multiple TFs collaboratively participate in the transcriptional regulation.ResultsWe model the underlying regulatory interactions in terms of the directions (activation or repression) and their logical roles (necessary and/or sufficient) with a modified association rule mining approach, called mTRIM. The experiment on Yeast discovered 670 regulatory interactions, in which multiple TFs express their functions on common target genes collaboratively. The evaluation on yeast genetic interactions, TF knockouts and a synthetic dataset shows that our algorithm is significantly better than the existing ones.ConclusionsmTRIM is a novel method to infer TF collaborations in transcriptional regulation networks. mTRIM is available at http://www.msu.edu/~jinchen/mTRIM.

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The Genetic Landscape of a Cell

Cited by 2,000 publications

References 36 publications

Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process

Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process

Identification of phosphatase 2A‐like Sit4‐mediated signalling and ubiquitin‐dependent protein sorting as modulators of caffeine sensitivity in S. cerevisiae

Inferring transcription factor collaborations in gene regulatory networks

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