Poly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage

Fu, Huanyi; Liu, Rongdiao; Jia, Zixuan; Li, Ran; Zhu, Fengsen; Zhu, Wenxuan; Shao, Yangqing; Jin, Yiyang; Xue, Yuhua; Huang, Jun; Luo, Kunxin; Gao, Xiang; Lu, Huasong; Zhou, Qiang

doi:10.1038/s41556-022-00872-5

Cited by 48 publications

(28 citation statements)

References 66 publications

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“…The effect of paused Pol II highlighted another protein known to be involved in interactions between transcriptionrelated proteins, PARP1, as a potential regulator of enhancer-promoter contacts. 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).…”

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

confidence: 99%

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

confidence: 99%

RNA polymerase II and PARP1 shape enhancer-promoter contacts

Barshad

Lewis

Chivu

et al. 2022

Preprint

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“…A recent study demonstrated that inhibition of PARP1-mediated cyclin T PARylation induces the hyperphosphorylation of RNA Pol II CTD by CDK9 (ref. 52 ). It is interesting that our results showed that Tyr19Phe CDK9 failed to phosphorylate RNA Pol II at Ser2, resulting in a HR-deficient phenotype in PARP inhibitor-resistant cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting the ALK–CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex

et al. 2022

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Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor growth and improve survival of mice in PARP inhibitor-/platinum-resistant tumor xenograft models. Using human tumor biospecimens, we further demonstrate that phosphorylated ALK (p-ALK) expression is associated with resistance to PARP inhibitors and positively correlated with p-Tyr19-CDK9 expression. Together, our findings support a biomarker-driven, combinatorial treatment strategy involving ALK and PARP inhibitors to induce synthetic lethality in PARP inhibitor-/platinum-resistant tumors with high p-ALK–p-Tyr19-CDK9 expression.

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“…Unphosphorylated Pol II CTD is also incorporated into MED1 condensates at SEs, while phosphorylation of Pol II CTD by CDK7/9 can drive its transition from the transcription initiation hubs to transcription elongation/splicing hubs [ 111 ]. Moreover, phosphorylated Pol II CTD is also recruited into cyclin T1 (a key component of nuclear speckles) condensates for enhanced phosphorylation of Pol II CTD and efficient transcription elongation [ 109 , 110 ] ( Figure 4 B). Taken together, these findings paint a general picture in which LLPS-mediated TF condensates draw a large number of enhancer elements together to stabilize the condensed phase, while mediating the formation of transcription initiation hubs by recruiting unphosphorylated Pol II CTD in the presence of short RNA transcripts produced from initial transcription.…”

Section: Multi-scale Chromatin Organization and Dynamics Mediated By ...mentioning

confidence: 99%

Phase Separation-Mediated Chromatin Organization and Dynamics: From Imaging-Based Quantitative Characterizations to Functional Implications

Sielaff²,

Zhao³

2022

IJMS

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As an effective and versatile strategy to compartmentalize cellular components without the need for lipid membranes, phase separation has been found to underpin a wide range of intranuclear processes, particularly those involving chromatin. Many of the unique physico-chemical properties of chromatin-based phase condensates are harnessed by the cell to accomplish complex regulatory functions in a spatially and temporally controlled manner. Here, we survey key recent findings on the mechanistic roles of phase separation in regulating the organization and dynamics of chromatin-based molecular processes across length scales, packing states and intranuclear functions, with a particular emphasis on quantitative characterizations of these condensates enabled by advanced imaging-based approaches. By illuminating the complex interplay between chromatin and various chromatin-interacting molecular species mediated by phase separation, this review sheds light on an emerging multi-scale, multi-modal and multi-faceted landscape that hierarchically regulates the genome within the highly crowded and dynamic nuclear space. Moreover, deficiencies in existing studies also highlight the need for mechanism-specific criteria and multi-parametric approaches for the characterization of chromatin-based phase separation using complementary techniques and call for greater efforts to correlate the quantitative features of these condensates with their functional consequences in close-to-native cellular contexts.

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Poly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage

Cited by 48 publications

References 66 publications

RNA polymerase II and PARP1 shape enhancer-promoter contacts

RNA polymerase II and PARP1 shape enhancer-promoter contacts

Targeting the ALK–CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex

Phase Separation-Mediated Chromatin Organization and Dynamics: From Imaging-Based Quantitative Characterizations to Functional Implications

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