Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer

Wang, Zebin; Grosskurth, Shaun; Cheung, Tony; Petteruti, Philip; Zhang, Jingwen; Wang, Xin; Wang, Wenxian; Gharahdaghi, Farzin; Wu, Joy T.; Su, Nancy; Howard, Ryan T.; Mayo, Michele; Widzowski, Dan; Scott, David A.; Johannes, Jeffrey W.; Lamb, Michelle L.; Lawson, Deborah; Dry, Jonathan R.; Lyne, Paul; Tate, Edward W.; Zinda, Michael; Mikule, Keith; Reimer, Corinne; Chen, Huawei

doi:10.1158/0008-5472.can-18-1362

Cited by 41 publications

(55 citation statements)

References 43 publications

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“…The high complexity of ADP-ribosyl associated pathways makes the involved proteins notoriously hard to study (Bonfiglio et al, 2020;Lüscher et al, 2018). While potent and specific inhibitors against many of the ADP-ribosyl transferases fundamentally helped to broaden our understanding of these enzymes (Durkacz et al, 1980;Huang et al, 2009;Kirby et al, 2018;Venkannagari et al, 2016;Wang et al, 2018), such inhibitors against ADP-ribosyl readers and erasers are still scarcely available or in early stages of development (Harrision et al, 2020;James et al, 2016;Liu et al, 2020;Palazzo and Ahel, 2018;Schuller et al, 2017). It was suggested that a possible bottleneck for the discovery of inhibitors is due to the lack of accessible high-throughput technologies (Schuller et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

A molecular toolbox for ADP-ribosyl binding proteins

Sowa

Galera‐Prat

Wazir

et al. 2021

Preprint

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Proteins interacting with ADP-ribosyl groups are often involved in disease-related pathways or in viral infections, which makes them attractive targets for the development of inhibitors. Our goal was to develop a robust and accessible assay technology that is suitable for high-throughput screening and applicable to a wide range of proteins acting as either hydrolysing or non-hydrolysing binders of mono- and poly-ADP-ribosyl groups. As a foundation of our work, we developed a C-terminal protein fusion tag based on a Gi protein alpha subunit peptide (GAP), which allows for site-specific introduction of cysteine-linked mono- and poly-ADP-ribosyl groups as well as chemical ADP-ribosyl analogs. By fusion of the GAP-tag and ADP-ribosyl binders to fluorescent proteins, we were able to generate robust FRET signals and the interaction with 22 previously described ADP-ribosyl-binders was confirmed. To demonstrate the applicability of this binding assay for high-throughput screening, we utilized it to screen for inhibitors of the SARS-CoV-2 nsp3 macrodomain and identified the drug suramin as a moderate yet unspecific inhibitor of this protein. To complement the binding technology, we prepared high-affinity ADP-ribosyl binders fused to a nanoluciferase, which enabled simple blot-based detection of mono- and poly-ADP-ribosylated proteins. These tools can be expressed recombinantly in E. coli using commonly available agents and will help to investigate ADP-ribosylation systems and aid in drug discovery.

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Section: Discussionmentioning

confidence: 99%

A molecular toolbox for ADP-ribosyl binding proteins

Sowa

Galera‐Prat

Wazir

et al. 2021

Preprint

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“…On the other hand, new studies showed that PARP6 could maintain centrosome integrity via the direct MARylation of Chk1 and modulation of its activity in breast cancer cells. Treatment with AZ0108, a PARP6 inhibitor, led to apoptosis in a subset of breast cancer cells [146,147]. These studies suggested the dual role of PARP6 in different types of tumors.…”

Section: Other Parps In the Regulation Of Human Diseasesmentioning

confidence: 99%

The Role of PARPs in Inflammation—And Metabolic—Related Diseases: Molecular Mechanisms and Beyond

Wang

Zhang

et al. 2019

Cells

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Poly(ADP-ribosyl)ation (PARylation) is an essential post-translational modification catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes. Poly(ADP-ribose) polymerase 1 (PARP1) is a well-characterized member of the PARP family. PARP1 plays a crucial role in multiple biological processes and PARP1 activation contributes to the development of various inflammatory and malignant disorders, including lung inflammatory disorders, cardiovascular disease, ovarian cancer, breast cancer, and diabetes. In this review, we will focus on the role and molecular mechanisms of PARPs enzymes in inflammation- and metabolic-related diseases. Specifically, we discuss the molecular mechanisms and signaling pathways that PARP1 is associated with in the regulation of pathogenesis. Recently, increasing evidence suggests that PARP inhibition is a promising strategy for intervention of some diseases. Thus, our in-depth understanding of the mechanism of how PARPs are activated and how their signaling downstream effecters can provide more potential therapeutic targets for the treatment of the related diseases in the future is crucial.

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“…31 MARylation of cell cycle checkpoint kinase 1 (Chk1) hinders the phosphorylation of Chk1S345, and the removal of MARylation leads to mitotic signaling defects. 32 In addition, MARylation of the hydrolases PARG, 33 TARG1, 34 MACROD2 35 and PARP1 36 shifts their activities toward cell damage repair. During the repair process, the export of MACROD2 from the nucleus to the cytoplasm increases.…”

mentioning

confidence: 99%

Analysis of Mono-ADP-Ribosylation Levels in Human Colorectal Cancer

Wang¹,

Li²,

Xiao³

et al. 2021

CMAR

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Background: Colorectal cancer remains a major public health problem with high morbidity and mortality rates. In the search for the mechanisms of colorectal cancer occurrence and development, increasing attention has been focused on epigenetics. The overall level of Mono-ADP-ribosylation, an epigenetic, has not been investigated now. The aim of our study was to analysis of the overall level of mono-ADP-ribosylation in colorectal cancer. Methods: Immunohistochemistry was used to investigate the level of mono-ADPribosylation in colorectal cancer and normal colorectal adjacent tissue from 64 CRC patients. The data of patient demographic, clinical and pathological characteristics were acquired and analyzed. Results: Mono-ADP-ribosylation was present in both colorectal adenocarcinoma and normal colorectal tissue. The overall level of mono-ADP-ribosylation in colorectal cancer was significantly higher than that in normal colorectal adjacent tissue. In the nucleus, the majority of samples in the high-level group were colorectal adenocarcinoma (55/64), but the opposite was true for normal colorectal tissues (7/32). In particular, increases in the level of mono-ADP-ribosylation in the cytoplasm of colorectal cancer cells was associated with a greater invasion depth of the tumor. Conclusion: The increased level of mono-ADP-ribosylation in colorectal cancer enhances tumor invasion, which suggests that mono-ADP-ribosylation is involved in the development of colorectal cancer and may become a new direction to solve the problem of colorectal cancer.

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Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer

Cited by 41 publications

References 43 publications

A molecular toolbox for ADP-ribosyl binding proteins

A molecular toolbox for ADP-ribosyl binding proteins

The Role of PARPs in Inflammation—And Metabolic—Related Diseases: Molecular Mechanisms and Beyond

Analysis of Mono-ADP-Ribosylation Levels in Human Colorectal Cancer

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