Inhibitors of PARP: Number crunching and structure gazing

Rudolph, Johannes; Jung, Karen; Luger, Karolin

doi:10.1073/pnas.2121979119

Cited by 76 publications

(62 citation statements)

References 101 publications

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“…As expected, during transcription of the nucleosomal templates in the absence of PARP1, characteristic pauses were observed at the positions + (11)(12)(13)(14)(15), + (26)(27), + (35)(36)(37) and + (45)(46)(47)(48) bp from the promoter-proximal nucleosome boundary (Figure 1b) [28]. Transcription in the presence of non-PARylated PARP1 (in the absence of NAD+) results in a moderate decrease in the overall efficiency of nucleosome traversal by yPol II and an increase of pausing at positions + (28)(29) and +(38-40) (Figure 1b).…”

Section: Parp1 Facilitates Transcription Through the Nucleosome By Po...supporting

confidence: 81%

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Human PARP1 Facilitates Transcription through a Nucleosome and Histone Displacement by Pol II In Vitro

Kotova

Hsieh

Chang

et al. 2022

IJMS

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Human poly(ADP)-ribose polymerase-1 (PARP1) is a global regulator of various cellular processes, from DNA repair to gene expression. The underlying mechanism of PARP1 action during transcription remains unclear. Herein, we have studied the role of human PARP1 during transcription through nucleosomes by RNA polymerase II (Pol II) in vitro. PARP1 strongly facilitates transcription through mononucleosomes by Pol II and displacement of core histones in the presence of NAD+ during transcription, and its NAD+-dependent catalytic activity is essential for this process. Kinetic analysis suggests that PARP1 facilitates formation of “open” complexes containing nucleosomal DNA partially uncoiled from the octamer and allowing Pol II progression along nucleosomal DNA. Anti-cancer drug and PARP1 catalytic inhibitor olaparib strongly represses PARP1-dependent transcription. The data suggest that the negative charge on protein(s) poly(ADP)-ribosylated by PARP1 interact with positively charged DNA-binding surfaces of histones transiently exposed during transcription, facilitating transcription through chromatin and transcription-dependent histone displacement/exchange.

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Section: Parp1 Facilitates Transcription Through the Nucleosome By Po...supporting

confidence: 81%

“…Core histones [9] and linker histone H1 [10] are among the targets for PARylation. Some inhibitors of PARP1 enzymatic activity are important anticancer compounds [11,12]. In particular, inhibition of PARP1 by olaparib induces synthetic lethality in tumor cells deficient in enzymes involved in homologous recombination DNA repair [13,14].…”

Section: Introductionmentioning

confidence: 99%

Human PARP1 Facilitates Transcription through a Nucleosome and Histone Displacement by Pol II In Vitro

Kotova

Hsieh

Chang

et al. 2022

IJMS

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“…S10 ), should also be investigated, because it remains unclear whether this hypersensitivity is attributable to the tuft cell-like phenotype. Finally, HPF1, a novel PARP1/2-interacting protein [ 41 ] and strong modifier of PARPi sensitivity [ 52 ], warrants study in tuft cell-like NECs, although on average, they did not show abnormal HPF1 expression levels or HPF1 mutations in public datasets [ 24 , 27 ] (not shown).…”

Section: Discussionmentioning

confidence: 99%

Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities

Yamada

Belharazem-Vitacolonnna

Bohnenberger

et al. 2022

Cell Death Dis

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Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10–20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited “lineage ambiguity” as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC.

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“…To evaluate the benefits of PARPi in a/m UCB, it is urgent to identify novel and reliable biomarkers that can detect HRD in tumor specimens or the germlines. Deleterious mutations in BRCA1 or BRCA2 gene are a canonical example of HRD [ 1 2 3 4 17 ]. However, HRD can also occur through methylation changes in other HRR genes that decrease gene expression or epigenetic silencing without canonical HRR gene mutations.…”

Section: The Need To Indentify Predictive Biomarkers For Optimal Use ...mentioning

confidence: 99%

Clinical implications and practical considerations for poly-ADP-ribose polymerase inhibitors as a new horizon for the management of urothelial carcinoma of the bladder

Lee

Seo

2022

Investig Clin Urol

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Inhibitors of PARP: Number crunching and structure gazing

Cited by 76 publications

References 101 publications

Human PARP1 Facilitates Transcription through a Nucleosome and Histone Displacement by Pol II In Vitro

Human PARP1 Facilitates Transcription through a Nucleosome and Histone Displacement by Pol II In Vitro

Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities

Clinical implications and practical considerations for poly-ADP-ribose polymerase inhibitors as a new horizon for the management of urothelial carcinoma of the bladder

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