DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes

Basu, Soumalee; Barad, Mahesh; Yadav, Dipika; Nandy, Arijit; Mukherjee, Biswarup; Sarkar, Jit; Chakrabarti, Partha; Mukhopadhyay, Satinath; Biswas, Debabrata

doi:10.1073/pnas.1912375117

Cited by 23 publications

(16 citation statements)

References 35 publications

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“…In cells, the levels of active SEC are modulated by targeted degradation of the AFF4 scaffold and ELL1/2 subunits by the E3 ubiquitin ligase SIAH1 (52)(53)(54)(55). Consistent with this, depletion of SIAH1 in MRC5 cells resulted in strongly (ϳ5-fold) enhanced levels of AFF4 protein and a concomitant increase in transcription of HSV IE (ICP4 and ICP27) genes (Fig.…”

Section: Suppression Of Hsv Ie Gene Expression and Lytic Infection By Inhibition Of The Secsupporting

confidence: 66%

Inhibition of the Super Elongation Complex Suppresses Herpes Simplex Virus Immediate Early Gene Expression, Lytic Infection, and Reactivation from Latency

Alfonso

Arbuckle

Vogel

et al. 2020

mBio

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Induction of herpes simplex virus (HSV) immediate early (IE) gene transcription promotes the initiation of lytic infection and reactivation from latency in sensory neurons. IE genes are transcribed by the cellular RNA polymerase II (RNAPII) and regulated by multiple transcription factors and coactivators. The HCF-1 cellular coactivator plays a central role in driving IE expression at multiple stages through interactions with transcription factors, chromatin modulation complexes, and transcription elongation components, including the active super elongation complex/P-TEFb (SEC-P-TEFb). Here, we demonstrate that the SEC occupies the promoters of HSV IE genes during the initiation of lytic infection and during reactivation from latency. Specific inhibitors of the SEC suppress viral IE expression and block the spread of HSV infection. Significantly, these inhibitors also block the initiation of viral reactivation from latency in sensory ganglia. The potent suppression of IE gene expression by SEC inhibitors indicates that transcriptional elongation represents a determining rate-limiting stage in HSV IE gene transcription and that the SEC plays a critical role in driving productive elongation during both phases of the viral life cycle. Most importantly, this supports the model that signal-mediated induction of SEC-P-TEFb levels can promote reactivation of a population of poised latent genomes. IMPORTANCE HSV infections can cause pathologies ranging from recurrent lesions to significant ocular disease. Initiation of lytic infection and reactivation from latency in sensory neurons are dependent on the induced expression of the viral immediate early genes. Transcription of these genes is controlled at multiple levels, including modulation of the chromatin state of the viral genome and appropriate recruitment of transcription factors and coactivators. Following initiation of transcription, IE genes are subject to a key regulatory stage in which transcriptional elongation rates are controlled by the activity of the super elongation complex. Inhibition of the SEC blocks both lytic infection and reactivation from latency in sensory neurons. In addition to providing insights into the mechanisms controlling viral infection and reactivation, inhibitors of critical components such as the SEC may represent novel antivirals.

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Section: Suppression Of Hsv Ie Gene Expression and Lytic Infection By Inhibition Of The Secsupporting

confidence: 66%

Inhibition of the Super Elongation Complex Suppresses Herpes Simplex Virus Immediate Early Gene Expression, Lytic Infection, and Reactivation from Latency

Alfonso

Arbuckle

Vogel

et al. 2020

mBio

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“…Lysine acetylation of non-histone proteins competes with ubiquitination to affect protein stability [ 9 ], and therefore we next examined the effect of SIRT2 expression on PARP1 levels. We found that increasing levels of SIRT2 overexpression led to a gradual reduction in PARP1 levels ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous study revealed that PARP1 as the major factor in oxidative stress-induced cardiovascular injury undergoes ubiquitination by E3 ubiquitin ligase WW domain-containing protein 2 (WWP2) [ 6 , 7 ]. However, lysine deacetylation of non-histone proteins promotes ubiquitination to affect protein stability [ 9 ]. Deacetylation of PARP1, the regulatory mechanisms of PARP1 deacetylation, and the crosstalk of PARP1 post-translational modifications remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Deacetylation-dependent regulation of PARP1 by SIRT2 dictates ubiquitination of PARP1 in oxidative stress-induced vascular injury

Zhang¹,

Zhang²,

Wu³

et al. 2021

Redox Biology

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Poly(ADP-ribose) polymerase 1 (PARP1) has a major regulatory role in cardiovascular disease. However, inhibiting PARP1 activity does not significantly improve clinical outcomes of cardiovascular disease, which suggests that the regulatory mechanism of PARP1 in cardiovascular disease is unclear. Here, we focused on deacetylation regulatory mechanisms of PARP1 and crosstalk of PARP1 post-translational modifications. We uncovered the crucial molecular interactions and protein modifications of deacetylase Sirtuin 2 (SIRT2) and PARP1 in vascular damage. The results showed that SIRT2 was involved in this process and oxidative stress damage factor PARP1 was a novel physiological substrate of SIRT2. SIRT2 interacted with PARP1 at the PARP-A-helical domain and deacetylated the K249 residue of PARP1. Furthermore, SIRT2 promoted ubiquitination of the K249 residue of PARP1 via mobilization of the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2), which led to proteasome-mediated degradation of PARP1. Knockout of SIRT2 in mice and cells increased PARP1 acetylation and decreased PARP1 ubiquitination, which in turn aggravated oxidative stress-induced vascular injury and remodeling. Conversely, overexpression of SIRT2 in mice and cells decreased PARP1 acetylation, increased PARP1 ubiquitination, and relieved oxidative stress-induced vascular injury and remodeling. Overall, this study revealed a previously unrecognized mechanistic link between SIRT2 and PARP1 in the regulation of oxidative stress-induced vascular injury.

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“…This makes sense, as CCAR proteins interact with steroid hormone receptors (Wu et al 2014). Additional studies with CCAR2 RNAi performed in HEK 293 human embryonic kidney cells confirmed the involvement of CCAR2 in regulating genes involved in metabolism (Basu et al 2020;Close et al 2012).…”

Section: Introductionmentioning

confidence: 92%

CCAR-1 has a novel role in regulating the Caenorhabditis elegans germline

Deonarine

2021

Preprint

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The Cell Division Cycle and Apoptosis Regulator (CCAR) protein family members are putative transcription regulators that have been characterized for modulating the cell cycle, apoptosis, metabolism, and the heat shock response. Mammals have two CCAR family members, CCAR1 and CCAR2/DBC1, that evolved from the founding family member CCAR-1 that is expressed in Caenorhabditis elegans. Mammalian CCAR2, the most well-studied family member, has been shown to regulate genes involved in metabolism in cultured cells. However, the regulation of gene expression by CCAR family members at an organismal level is unknown. Here, we use whole transcriptome RNA sequencing to examine the effects of CCAR-1 on gene expression in Caenorhabditis elegans. We show that CCAR-1 regulates germline transcription, reproduction, lifespan, and DNA-damage induced apoptosis. This study shows the role of CCAR-1 in vital physiological functions in the C. elegans germline that have not been investigated before.

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DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes

Cited by 23 publications

References 35 publications

Inhibition of the Super Elongation Complex Suppresses Herpes Simplex Virus Immediate Early Gene Expression, Lytic Infection, and Reactivation from Latency

Inhibition of the Super Elongation Complex Suppresses Herpes Simplex Virus Immediate Early Gene Expression, Lytic Infection, and Reactivation from Latency

Deacetylation-dependent regulation of PARP1 by SIRT2 dictates ubiquitination of PARP1 in oxidative stress-induced vascular injury

CCAR-1 has a novel role in regulating the Caenorhabditis elegans germline

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