GFZF, a Glutathione <i>S</i>-Transferase Protein Implicated in Cell Cycle Regulation and Hybrid Inviability, Is a Transcriptional Coactivator

Baumann, Douglas G.; Dai, Mu Shui; Lu, Hua; Gilmour, David S.

doi:10.1128/mcb.00476-17

Cited by 15 publications

(23 citation statements)

References 49 publications

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“…TRF2 was recently shown to interact with M1BP (motif 1 binding protein) (57). Interestingly, M1BP was recently demonstrated to interact with GFZF, a nuclear glutathione S-transferase protein that has been implicated in cell cycle regulation (58). We suspected that GFZF may interact with TRF2.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, using FLAG immuno-affinity purification from FLAG-HA TRF2-inducible S2R+ cells followed by mass spectrometry analysis, we discovered that both M1BP and GFZF are in complex with the evolutionarily conserved TRF2 (also known as short TRF2), but not with the long Drosophila -only TRF2 isoform or with TBP (Table 3 and Additional file 8: Table S3). This prompted us to examine the occupancy of TRF2, M1BP and GFZF in the vicinity of the TSSs (−100 to +100 relative to the TSS) of TRF2-regulated cyclin genes, using publicly available TRF2, M1BP and GFZF ChIP-exo analyses in Drosophila S2R+ cells (GSE97841, GSE105009) (57, 58). We examined the number of bound sites, the average peak scores and the maximum peak scores of cyclin genes and several ribosomal protein genes for comparison (Table 4).…”

Section: Resultsmentioning

confidence: 99%

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The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

Kedmi

Sloutskin

Epstein

et al. 2020

Preprint

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26Background: Diverse biological processes and transcriptional programs are 27 regulated by RNA polymerase II (Pol II), which is recruited by the general transcription 28 machinery to the core promoter to initiate transcription. TRF2 (TATA-box-binding 29 protein-related factor 2) is an evolutionarily conserved general transcription factor that 30 is essential for embryonic development of Drosophila melanogaster, C. elegans, 31 zebrafish and Xenopus. Nevertheless, the cellular processes that are regulated by 32 TRF2 are largely underexplored. 33Results: Here, using Drosophila Schneider cells as a model, we discovered that TRF2 34 regulates apoptosis and cell cycle progression. We show that TRF2 knockdown 35 results in increased expression of distinct pro-apoptotic genes and induces apoptosis. 36Using flow cytometry, high-throughput microscopy and advanced imaging-flow 37 cytometry, we demonstrate that TRF2 regulates cell cycle progression and exerts 38 distinct effects on G1 and specific mitotic phases. RNA-seq analysis revealed that 39 TRF2 controls the expression of Cyclin E and the mitotic cyclins, Cyclin A, Cyclin B 40 and Cyclin B3, but not Cyclin D or Cyclin C. To identify proteins that could account for 41 the observed regulation of these cyclin genes, we searched for TRF2-interacting 42 proteins. Interestingly, mass spectrometry analysis of TRF2-containing complexes 43 identified GFZF, a nuclear glutathione S-transferase implicated in cell cycle regulation, 44and Motif 1 binding protein (M1BP). TRF2 has previously been shown to interact with 45 M1BP and M1BP has been shown to interact with GFZF. Furthermore, available ChIP-46 exo data revealed that TRF2, GFZF and M1BP co-occupy the promoters of TRF2-47 with TRF2, it is TRF2, rather than GFZF or M1BP, that is the main factor regulating 50 the expression of Cyclin E and the mitotic cyclins. 51 Conclusions: Our findings uncover a critical and unanticipated role of a general 52 transcription factor as a key regulator of cell cycle and apoptosis. 53 54 Keywords 55 Basal transcription machinery, RNA polymerase II, gene expression, TATA box-56 binding protein (TBP), TBP-related factor 2 (TRF2), cyclin genes. 57 58 BACKGROUND 59 Multiple biological processes and transcriptional programs are regulated by RNA 60 polymerase II (Pol II). The initiation of transcription of protein-coding genes and 61 distinct non-coding RNAs occurs following the recruitment of Pol II to the core 62 promoter region by the general/basal transcription machinery (1-4). The core 63promoter, which directs accurate initiation of transcription and encompasses the 64 transcription start site (TSS), may contain short DNA sequence elements/motifs, 65 which confer specific properties to the core promoter (1, 4-10). The first step in the 66 recruitment of Pol II to initiate transcription is the binding of TFIID, which is 67 composed of TATA-box-binding protein (TBP) and TBP-associated factors. 68Remarkably, although TBP is considered a universal general transcription factor, 69 robust Pol II transc...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

Kedmi

Sloutskin

Epstein

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Though gfzf is a chromatin associated factor that has many binding sites in the genome (Baumann et al 2018), it is not clear if this property is consistent between D. melanogaster and D. simulans. To determine whether gfzf mel and gfzf sim show differences in chromatin localization patterns, we developed an antibody that can recognize the GFZF protein from both species (Supplemental Figure 1).…”

Section: Different Localization Patterns Of Gfzf At D Melanogaster Amentioning

confidence: 99%

“…gfzf has been identified repeatedly in several genetic screens, including those designed to identify suppressors of the Killer-of-prune system (Provost et al 2006), cell-cycle regulation (Ambrus et al 2009), DNA damage induced cell-cycle checkpoints (Kondo and Perrimon 2011), Ras/MAPK signaling (Ashton-Beaucage et al 2014), and Polycomb complex regulation (Gonzalez et al 2014). One potential explanation for the role of gfzf in such a variety of processes comes from a recent study where gfzf was identified as a transcriptional co-activator through an association with Motif1 binding protein (M1BP), and shown to bind the transcriptional start sites of genes relevant to the genetic screens where gfzf was identified as a hit (Baumann et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Altered chromatin localization of hybrid lethality proteins inDrosophila

Cooper

Lukacs²,

Reich

et al. 2018

Preprint

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Understanding hybrid incompatibilities is a fundamental pursuit in evolutionary genetics. In crosses between Drosophila melanogaster females and Drosophila simulans males, the interaction of at least three genes is necessary for hybrid male lethality: Hmr mel , Lhr sim , and gfzf sim . All three hybrid incompatibility genes are chromatin associated factors. While HMR and LHR physically bind each other and function together in a single complex, the connection between either of these proteins and gfzf remains mysterious. Here, we investigate the allele specific chromatin binding patterns of gfzf. First, our cytological analyses show that there is little difference in protein localization of GFZF between the two species except at telomeric sequences. In particular, GFZF binds the telomeric retrotransposon repeat arrays, and the differential binding of GFZF at telomeres reflects the rapid changes in sequence composition at telomeres between D. melanogaster and D. simulans. Second, we investigate the patterns of GFZF and HMR co-localization and find that the two proteins do not normally co-localize in D. melanogaster. However, in inter-species hybrids, HMR shows extensive mis-localization to GFZF sites, and this altered localization requires the presence of gfzf sim . Third, we find by ChIP-Seq that over-expression of HMR and LHR within species is sufficient to cause HMR to mis-localize to GFZF binding sites, indicating that HMR has a natural low affinity for GFZF sites. Together, these studies provide the first insights into the different properties of gfzf between D. melanogaster and D. simulans as well as a molecular interaction between gfzf and Hmr in the form of altered protein localization.

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“…Hmr and Lhr are heterochromatin associated transcriptional repressors that physically bind each other and suppress the expression of transposable elements and repetitive DNA sequences (Thomae et al 2013;Satyaki et al 2014). gfzf is a general transcriptional co-activator for TATA-less genes along with M1BP (Baumann et al 2018). Recent work also demonstrates that Hmr mislocalizes to gfzf bound chromatin in F1 hybrids, indicating that they have the capability to interact with many other loci (Cooper et al 2018).…”

Section: Introductionmentioning

confidence: 99%

A triple-hybrid cross reveals a new hybrid incompatibility locus betweenD. melanogaster and D. sechellia

Cooper

Guo

Bladen

et al. 2019

Preprint

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Hybrid incompatibilities are the result of deleterious interactions between diverged genes in the progeny of two species. In Drosophila, crosses between female D. melanogaster and males from the D. simulans clade (D. simulans, D. mauritiana, D. sechellia) fail to produce hybrid F1 males. When attempting to rescue hybrid F1 males by depleting the incompatible allele of a previously identified hybrid incompatibility gene, we observed robust rescue in crosses of D. melanogaster to D. simulans or D. mauritiana, but no rescue in crosses to D. sechellia. To investigate the genetic basis of D. sechellia resistance to hybrid rescue, we designed a triple-hybrid cross to generate recombinant D. sechellia / D. simulans genotypes. We tested the ability of those genotypes to rescue hybrid males with D. melanogaster, and used whole genome sequencing to measure the D. sechellia / D. simulans allele frequency of viable F1 males. We found that recombinant genotypes were rescued when they contained two specific loci from D. simulansa region containing previously identified Lethal hybrid rescue (Lhr), and an unknown region of chromosome 3L which we name Sechellia aversion to hybrid rescue (Satyr). Our results show that the genetic basis for the recent evolution of this hybrid incompatibility is simple rather than a highly dispersed effect. Further, these data suggest that fixation of differences at Lhr after the split of the D. simulans clade strengthened the hybrid incompatibility between D. sechellia and D. melanogaster.

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GFZF, a Glutathione S-Transferase Protein Implicated in Cell Cycle Regulation and Hybrid Inviability, Is a Transcriptional Coactivator

Cited by 15 publications

References 49 publications

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

Altered chromatin localization of hybrid lethality proteins inDrosophila

A triple-hybrid cross reveals a new hybrid incompatibility locus betweenD. melanogaster and D. sechellia

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