Poly(Adp-Ribose) Drives Condensation of Fus Via a Transient Interaction

Rhine, Kevin; Dasovich, Morgan; Yoniles, Joseph; Badiee, Mohsen; Skanchy, Sophie; Ganser, Laura R.; Fare, Charlotte M.; Shorter, James; Leung, Anthony Kwan; Myong, Sua

doi:10.2139/ssrn.3890382

Cited by 5 publications

(19 citation statements)

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“…Consistent with this model, we found that changes in paused Pol II density near promoter TSSs were correlated with changes in enhancer-promoter contact frequency (Pearson’s R = 0.30, p = 0.003; taking median of 1-percentiles, see Methods), such that candidate enhancer-promoter pairs which accumulated more paused Pol II tended to lose fewer contacts. These findings suggest that PARP1 has at least two effects on enhancer-promoter contacts: The main effect, a stabilizing one, is independent of Pol II pausing and may depend on the contribution of PAR chains to macromolecular clustering ( 62 ). A weaker, destabilizing effect of PARP1 activity on enhancer-promoter contacts depends on PARylating NELFE ( 55 ) and accelerating Pol II escape from pause ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our observation that PAR chains catalyzed by PARP1 appear to stabilize enhancer-promoter contacts may be most compatible with a hub model. PAR chains facilitate macromolecular clustering via transient interactions between IDRs ( 62, 79 ). PARP1 also has an additional role in releasing paused Pol II into productive elongation by parylating NELFE ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

“…The main effect, a stabilizing one, is independent of Pol II pausing and may depend on the contribution of PAR chains to macromolecular clustering (62). A weaker, destabilizing effect of PARP1 activity on enhancer-promoter contacts depends on PARylating NELFE (55) and accelerating Pol II escape from pause (Fig.…”

Section: Parp1 Enzymatic Activity Has Two Opposite Effects On Enhance...mentioning

confidence: 97%

“…PARP1 is an enzyme which catalyzes the formation of poly (ADP-ribose) (PAR) chains, a post-translational modification added to transcription and chromatin-associated proteins (which are said to be "PARylated") near active enhancer and promoter regions (55)(56)(57)(58)(59)(60)(61). PAR chains play a critical role in driving the formation of molecular clusters through interactions with intrinsically disordered regions (IDRs) of proteins (62). Finally, inhibiting the enzymatic activity of PARP1 prevented changes in 3D distance between the Shh promoter and developmental enhancers in mouse embryos (16).…”

Section: Parp1 Enzymatic Activity Has Two Opposite Effects On Enhance...mentioning

confidence: 99%

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RNA polymerase II and PARP1 shape enhancer-promoter contacts

Barshad

Lewis

Chivu

et al. 2022

Preprint

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How enhancers control target gene expression over long genomic distances remains an important unsolved problem. Here we studied enhancer-promoter contact architecture and communication by integrating data from nucleosome-resolution genomic contact maps, nascent transcription, and perturbations to transcription-associated proteins and thousands of candidate enhancers. Contact frequency between functionally validated enhancer-promoter pairs was most enriched near the +1 and +2 nucleosomes at enhancers and target promoters, indicating that functional enhancer-promoter pairs spend time in close physical proximity. Blocking RNA polymerase II (Pol II) caused major disruptions to enhancer-promoter contacts. Paused Pol II occupancy and the enzymatic activity of poly (ADP-ribose) polymerase 1 (PARP1) stabilized enhancer-promoter contacts. Based on our findings, we propose an updated model that couples transcriptional dynamics and enhancer-promoter communication.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Parp1 Enzymatic Activity Has Two Opposite Effects On Enhance...mentioning

confidence: 97%

Section: Parp1 Enzymatic Activity Has Two Opposite Effects On Enhance...mentioning

confidence: 99%

See 2 more Smart Citations

RNA polymerase II and PARP1 shape enhancer-promoter contacts

Barshad

Lewis

Chivu

et al. 2022

Preprint

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“…PARP1 is an enzyme which catalyzes the formation of poly (ADP-ribose) (PAR) chains, a post-translational modi cation added to transcription and chromatin-associated proteins (which are said to be "PARylated") near active enhancer and promoter regions [55][56][57][58][59][60][61] . PAR chains play a critical role in driving the formation of molecular clusters through interactions with intrinsically disordered regions (IDRs) of proteins 62 . Finally, inhibiting the enzymatic activity of PARP1 prevented changes in 3D distance between the Shh promoter and developmental enhancers in mouse embryos 16 .…”

Section: Parp1 Enzymatic Activity Has Two Opposite Effects On Enhance...mentioning

confidence: 99%

RNA polymerase II and PARP1 shape enhancer-promoter contacts

Danko

Barshad

Lewis

et al. 2022

Preprint

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Molecular determinants of Karyopherin-β2 chaperone and disaggregation activity

Fare

Rhine

Lam

et al. 2022

Preprint

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Karyopherin-β2 (Kapβ2) is a nuclear-import receptor that recognizes proline-tyrosine nuclear localization signals (PY-NLSs) of diverse cytoplasmic cargo for transport to the nucleus. Kapβ2 cargo include several disease-linked RNA-binding proteins (RBPs) with prion-like domains (PrLDs), such as FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2. These RBPs with PrLDs are linked via pathology and genetics to debilitating degenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and multisystem proteinopathy (MSP). Remarkably, Kapβ2 prevents and reverses aberrant phase transitions of these cargo, which is cytoprotective. However, the molecular determinants of Kapβ2 that enable these activities remain poorly understood, particularly from the standpoint of nuclear-import receptor architecture. Kapβ2 is a superhelical protein comprised of 20 HEAT repeats. Here, we design truncated variants of Kapβ2 and assess their ability to antagonize FUS aggregation and toxicity in yeast and FUS condensation at the pure protein level and in human cells. We find that HEAT repeats 8-20 of Kapβ2 recapitulate all salient features of Kapβ2 activity. By contrast, Kapβ2 truncations lacking even a single cargo-binding HEAT repeat display reduced activity. Thus, we define a minimal Kapβ2 construct for delivery in adeno-associated viruses as a potential therapeutic for ALS/FTD, MSP, and related disorders.

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Poly(Adp-Ribose) Drives Condensation of Fus Via a Transient Interaction

Cited by 5 publications

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RNA polymerase II and PARP1 shape enhancer-promoter contacts

RNA polymerase II and PARP1 shape enhancer-promoter contacts

RNA polymerase II and PARP1 shape enhancer-promoter contacts

Molecular determinants of Karyopherin-β2 chaperone and disaggregation activity

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