Loss of Acinus Inhibits Oligonucleosomal DNA Fragmentation but Not Chromatin Condensation during Apoptosis

Joselin, Alvin; Schulze‐Osthoff, Klaus; Schwerk, Christian

doi:10.1074/jbc.m509859200

Cited by 48 publications

(51 citation statements)

References 48 publications

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“…Recently, it has been reported that knockdown of acinus in HeLa cells leads to a reduction in cell growth and inhibition of DNA fragmentation, but chromatin condensation was not significantly attenuated. 28 This finding underscores that acinus expression level is essential for cell growth and survival, consistent with our observations (Figure 3). Nonetheless, acinus and Mst1 remain intact in PKC-d knockout cells ( Figure 5).…”

Section: Discussionsupporting

confidence: 82%

Acinus-provoked protein kinase C δ isoform activation is essential for apoptotic chromatin condensation

et al. 2007

Cell Death Differ

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Histone H2B phosphorylation tightly correlates with chromatin condensation during apoptosis. The caspase-cleaved acinus (apoptotic chromatin condensation inducer in the nucleus) provokes chromatin condensation in the nucleus, but the molecular mechanism accounting for this effect remains elusive. Here, we report that the active acinus p17 fragment initiates H2B phosphorylation and chromatin condensation by activating protein kinase C d isoform (PKC-d). We show that p17 binds to both Mst1 and PKC-d, which is upregulated by apoptotic stimuli, enhancing their kinase activities. Acinus mutant susceptible to degradation elicits stronger chromatin condensation and higher H2B phosphorylation than wild-type acinus. Dominant-negative PKC-d but not Mst1 robustly blocks acinus-initiated H2B phosphorylation. Surprisingly, depletion of Mst1 triggers caspase-3 activation, provoking H2B phosphorylation through activating PKC-d. Chromatin condensation, a hallmark of apoptosis, is associated with histone H2B phosphorylation. Phosphorylation of H2B is usually negligible in both quiescent and growth states, but it is markedly stimulated when chromatin condensation and nucleosomal DNA fragmentation is initiated.1 Allis and coworkers demonstrated that phosphorylation of H2B at serine 14 by caspase-cleaved Mst1 tightly correlates with cells undergoing programmed cell death.2 Histone 2B serine 14 (H2BS14) phosphorylation has also been consistently accumulated at DNA double-strand breaks, indicative of its important role in apoptosis.3 Chromatin condensation can be induced by a nuclear protein called acinus (apoptotic chromatin condensation inducer in the nucleus), which is cleaved during apoptosis. 4 Acinus is cleaved by caspases on both its N-and C-termini, producing a p17 active form (amino acids (a.a.) 987-1093 in -L isoform), which elicits chromatin condensation in the absence of caspase-3. Recently, we showed that Akt phosphorylates acinus on serine 422 and 573, resulting in its resistance to caspase cleavage in the nucleus and the inhibition of acinus-dependent chromatin condensation. Thus, Akt inhibits chromatin condensation during apoptosis by phosphorylating acinus in the nucleus, revealing a specific mechanism by which nuclear Akt promotes cell survival. 5 However, the molecular mechanism as to how p17 couples to chromatin condensation remains elusive.MST1 (mammalian Ste20-like kinase 1) is ubiquitously expressed. MST1 contains a Ste20-related kinase catalytic domain in the amino-terminal segment (a.a. 30-270), followed by a noncatalytic tail that contains successively an autoinhibitory domain (a.a. 331-394), a dimerization domain (after a.a. 431), and a nuclear localization signal at the COOH terminus.6-8 MST1 is predominantly cytoplasmic but cycles continuously through the nucleus. Mst1 is activated and cleaved by a broad range of stimuli in various cell types, which suggests that it is a common component in the diverse signaling pathways leading to apoptosis.9 Overexpression of Mst1 in some cell types induces apoptotic fe...

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Section: Discussionsupporting

confidence: 82%

Acinus-provoked protein kinase C δ isoform activation is essential for apoptotic chromatin condensation

et al. 2007

Cell Death Differ

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“…The DFFA transcript containing the retained intron encodes a shorter DFFA protein isoform (DFFA-S/ ICAD-S), which does not work as a chaperone for the caspase-activated DNase (DFFB or CAD) and consequently impairs the DNA fragmentation induced by apoptotic stimuli (Li et al 2005). The splicing changes toward the DFFA-S protein isoform observed in Acinus-depleted cells can thus help to explain the previously observed DNA fragmentation inhibition due to Acinus loss (Joselin et al 2006;Rigou et al 2009). …”

Section: Acinus and Eif4a3 Splicing Co-regulationmentioning

confidence: 88%

The RNA-binding profile of Acinus, a peripheral component of the exon junction complex, reveals its role in splicing regulation

Rodor

Pan

Blencowe

et al. 2016

RNA

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Acinus (apoptotic chromatin condensation inducer in the nucleus) is an RNA-binding protein (RBP) originally identified for its role in apoptosis. It was later found to be an auxiliary component of the exon junction complex (EJC), which is deposited at exon junctions as a consequence of pre-mRNA splicing. To uncover the cellular functions of Acinus and investigate its role in splicing, we mapped its endogenous RNA targets using the cross-linking immunoprecipitation protocol (iCLIP). We observed that Acinus binds to pre-mRNAs, associating specifically to a subset of suboptimal introns, but also to spliced mRNAs. We also confirmed the presence of Acinus as a peripheral factor of the EJC. RNA-seq was used to investigate changes in gene expression and alternative splicing following siRNA-mediated depletion of Acinus in HeLa cells. This analysis revealed that Acinus is preferentially required for the inclusion of specific alternative cassette exons and also controls the faithful splicing of a subset of introns. Moreover, a large number of splicing changes can be related to Acinus binding, suggesting a direct role of Acinus in exon and intron definition. In particular, Acinus regulates the splicing of DFFA/ICAD transcript, a major regulator of DNA fragmentation. Globally, the genome-wide identification of RNA targets of Acinus revealed its role in splicing regulation as well as its involvement in other cellular pathways, including cell cycle progression. Altogether, this study uncovers new cellular functions of an RBP transiently associated with the EJC.

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“…On the other hand, RNPS1 is also able to interact with SAP18 and Acinus in vivo to form a protein complex, termed the apoptosis-and splicing-associated protein (ASAP) (Schwerk et al 2003). Intriguingly, Acinus has been suggested to be involved in apoptotic DNA cleavage although the exact mechanism remains elusive (Joselin et al 2006). Taken together, these documented properties of RNPS1 are consistent with another possibility: that excess RNPS1 influences the expression or activity of some unknown factor(s), and this in turn complements the function of ASF/SF2 in preventing transcriptional R-looping and/or R-loop-induced DNA damage.…”

Section: Discussionmentioning

confidence: 99%

The RNA binding protein RNPS1 alleviates ASF/SF2 depletion-induced genomic instability

Niu²,

Manley³

2007

RNA

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Formation of transcription-induced R-loops poses a critical threat to genomic integrity throughout evolution. We have recently shown that the SR protein ASF/SF2 prevents R-loop formation in vertebrates by cotranscriptionally binding to nascent mRNA precursors to prevent their reassociation with template DNA. Here, we identify another RNA binding protein, RNPS1, that when overexpressed strongly suppresses the high molecular weight (HMW) DNA fragmentation, hypermutation, and G2 cell cycle arrest phenotypes of ASF/SF2-depleted cells. Furthermore, ablation of RNPS1 by RNA interference in HeLa cells leads to accumulation of HMW DNA fragments. As ASF/SF2 depletion does not influence RNPS1 expression, and RNPS1 cannot compensate for ASF/SF2 function in splicing, our data suggest that RNPS1 is able to function together with ASF/SF2 to form RNP complexes on nascent transcripts, and thereby prevent formation of transcriptional R-loops.

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Loss of Acinus Inhibits Oligonucleosomal DNA Fragmentation but Not Chromatin Condensation during Apoptosis

Cited by 48 publications

References 48 publications

Acinus-provoked protein kinase C δ isoform activation is essential for apoptotic chromatin condensation

Acinus-provoked protein kinase C δ isoform activation is essential for apoptotic chromatin condensation

The RNA-binding profile of Acinus, a peripheral component of the exon junction complex, reveals its role in splicing regulation

The RNA binding protein RNPS1 alleviates ASF/SF2 depletion-induced genomic instability

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