Document Type
Article
Publication Date
12-1-2018
Abstract
PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1-mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance "BRCA-ness". These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting.
Recommended Citation
Schiewer, M J; Mandigo, Amy C.; Gordon, Nicolas; Huang, Fangjin; Gaur, Sanchaika; de Leeuw, Renée; Zhao, Shuang G; Evans, Joseph; Han, Sumin; Parsons, Theodore; Birbe, Ruth; McCue, Peter; McNair, Christopher; Chand, Saswati N.; Cendon-Florez, Ylenia; Gallagher, Peter; McCann, Jennifer J; Poudel Neupane, Neermala; Shafi, Ayesha A; Dylgjeri, Emanuela; Brand, Lucas J; Visakorpi, Tapio; Raj, Ganesh V; Lallas, Costas D.; Trabulsi, Edouard J; Gomella, Leonard G; Dicker, Adam MD, PhD; Kelly, William Kevin; Leiby, Benjamin E; Knudsen, Beatrice; Feng, Felix Y; and Knudsen, Karen E, "PARP-1 regulates DNA repair factor availability." (2018). Department of Cancer Biology Faculty Papers. Paper 145.
https://jdc.jefferson.edu/cbfp/145
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
30467127
Comments
This article has been peer reviewed. It was published in: EMBO Molecular Medicine.
Volume 10, Issue 12, December 2018, Article number e8816.
The published version is available at DOI: 10.15252/emmm.201708816
Copyright © 2018 The Authors
Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.