Drosophila SIN3 Isoforms Interact with Distinct Proteins and Have Unique Biological Functions

Spain, Marla M.; Caruso, Joseph A.; Swaminathan, Aishwarya; Pile, Lori A.

doi:10.1074/jbc.m110.130245

Cited by 40 publications

(66 citation statements)

References 70 publications

(113 reference statements)

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“…The histone demethylase Little imaginal discs (LID) was found to be a component of a SIN3 complex [71, 72]. Similar to what we have observed in the Sin3A knockdown flies, male flies expressing a demethylase mutant of LID are sensitive to paraquat treatment and have reduced longevity as compared to wild type controls [73].…”

Section: Discussionmentioning

confidence: 70%

SIN3 is critical for stress resistance and modulates adult lifespan

Barnes

Bhat

Unnikrishnan

et al. 2014

Aging

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Coordinate control of gene activity is critical for fitness and longevity of an organism. The SIN3 histone deacetylase (HDAC) complex functions as a transcriptional repressor of many genes. SIN3-regulated genes include those that encode proteins affecting multiple aspects of mitochondrial function, such as energy production and stress responsiveness, important for health maintenance. Here we used Drosophila melanogaster as a model organism to examine the role of SIN3 in the regulation of fitness and longevity. Adult flies with RNA interference (RNAi) induced knockdown expression of Sin3A have reduced climbing ability; an activity that likely requires fully functional mitochondria. Additionally, compared to wild type, adult Sin3A knockdown flies were more sensitive to oxidative stress. Interestingly, media supplementation with the antioxidant glutathione largely restored fly tolerance to oxidative stress. Although Sin3A knockdown flies exhibited decreased longevity compared to wild type, no significant changes in expression of many well-categorized aging genes were observed. We found, however, that Sin3A knockdown corresponded to a significant reduction in expression of genes encoding proteins involved in the de novo synthesis of glutathione. Taken together, the data support a model whereby SIN3 regulates a gene expression program required for proper mitochondrial function and effective stress response during adulthood.

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Section: Discussionmentioning

confidence: 70%

SIN3 is critical for stress resistance and modulates adult lifespan

Barnes

Bhat

Unnikrishnan

et al. 2014

Aging

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“…187 and 220 isoforms both interact with a core group of HDAC complex components that are conserved across species (13). Perhaps the SIN3 protein needs to be amid this core complex to be stable.…”

Section: Discussionmentioning

confidence: 99%

“…These isoforms vary only at the C terminus due to the presence of unique C-terminal exons, form distinct HDAC complexes, are functionally non-redundant, and are differentially expressed during development (timeline summarized in Fig. 1A (11,13)). SIN3 220 is the predominant isoform expressed in proliferating cells, whereas SIN3 187 expression is comparatively higher in differentiated tissue (11).…”

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confidence: 99%

Inter-isoform-dependent Regulation of the Drosophila Master Transcriptional Regulator SIN3

Chaubal

Todi

Pile

2016

Journal of Biological Chemistry

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SIN3 is a transcriptional corepressor that acts as a scaffold for a histone deacetylase (HDAC) complex. The SIN3 complex regulates various biological processes, including organ development, cell proliferation, and energy metabolism. Little is known, however, about the regulation of SIN3 itself. There are two major isoforms of Drosophila SIN3, 187 and 220, which are differentially expressed. Intrigued by the developmentally timed exchange of SIN3 isoforms, we examined whether SIN3 187 controls the fate of the 220 counterpart. Here, we show that in developing tissue, there is interplay between SIN3 isoforms: when SIN3 187 protein levels increase, SIN3 220 protein decreases concomitantly. SIN3 187 has a dual effect on SIN3 220. Expression of 187 leads to reduced 220 transcript, while also increasing the turnover of SIN3 220 protein by the proteasome. These data support the presence of a novel, inter-isoform-dependent mechanism that regulates the amount of SIN3 protein, and potentially the level of specific SIN3 complexes, during distinct developmental stages.Normal cell function requires precise and coordinated regulation of abundance, localization, and interaction of numerous proteins and associated factors. This systematic regulation is brought about by several synchronized processes that govern the production, subcellular location, and timely degradation of proteins. Key among these processes is the ubiquitin-proteasome system, which eliminates specific proteins at determined time points (1). Disturbance of the ubiquitin-proteasome system has serious consequences in cellular function that can directly cause cell death (2). This is especially true for controlling the steady-state levels of master regulatory proteins that regulate diverse transcriptional networks. Specific examples include the histone-modifying enzymes, which govern chromatin organization and thus regulate gene networks. Dysregulation of histone-modifying enzymes can be disastrous for the cell, because it not only leads to aberrant gene expression, but also affects genome stability (3).The SIN3 HDAC 2 complex, evolutionarily conserved from yeast to mammals, is one such important histone-modifying complex (4, 5). The protein SIN3 serves as a scaffold for the assembly of this complex (5). SIN3 is a master transcriptional regulator that, when deleted or mutated, causes embryonic lethality in Drosophila and mice (6 -9). Previous work from our laboratory showed that depletion of Drosophila SIN3 affects several biological processes, resulting in severe developmental defects, increased sensitivity to oxidative stress, and reduced life span (10 -12). Although many of the gene networks and biological processes regulated by SIN3 are known, the regulation of the SIN3 protein itself is poorly understood.In Drosophila, a single Sin3A gene gives rise to multiple SIN3 isoforms, SIN3 187, SIN3 190, and SIN3 220. These isoforms vary only at the C terminus due to the presence of unique C-terminal exons, form distinct HDAC complexes, are functionally non-redundant, ...

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“…26,27 HDAC1 associates with mSin3a, 22 histone binding proteins and mSin3a-associated polypeptides that influence histone deacetlyase activity. 28 In silico analysis of the amino acid sequence of the mouse mSin3a revealed an exact Cdk5 target motif at serine 861 and serine 860 in the human mSin3a. The kinase assays described in this report show Cdk5 directly phosphorylates both the recombinant mSin3a protein and endogenous mSin3a immunoprecipitated from T cells when either is used as a substrate in an in vitro Cdk5 kinase assay.…”

Section: Discussionmentioning

confidence: 99%

Cdk5 controls IL-2 gene expression via repression of the mSin3a-HDAC complex

2015

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Cyclin-dependent kinase 5 (Cdk5) is a unique member of a family of serine/threonine cyclin-dependent protein kinases. We previously demonstrated disruption of Cdk5 gene expression in mice impairs T-cell function and ameliorates T-cell-mediated neuroinflammation. Here, we show Cdk5 modulates gene expression during T-cell activation by impairing the repression of gene transcription by histone deacetylase 1 (HDAC1) through specific phosphorylation of the mSin3a protein at serine residue 861. Disruption of Cdk5 activity in T-cells enhances HDAC activity and binding of the HDAC1/mSin3a complex to the IL-2 promoter, leading to suppression of IL-2 gene expression. These data point to essential roles for Cdk5 in regulating gene expression in T-cells and transcriptional regulation by the co-repressor mSin3a.

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Drosophila SIN3 Isoforms Interact with Distinct Proteins and Have Unique Biological Functions

Cited by 40 publications

References 70 publications

SIN3 is critical for stress resistance and modulates adult lifespan

SIN3 is critical for stress resistance and modulates adult lifespan

Inter-isoform-dependent Regulation of the Drosophila Master Transcriptional Regulator SIN3

Cdk5 controls IL-2 gene expression via repression of the mSin3a-HDAC complex

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