@article{fa4c02deb5a3478997eb5e47958a69d0,
title = "PARP-1 regulates DNA repair factor availability",
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.",
keywords = "DNA repair, E2F1, PARP, transcription",
author = "Schiewer, {Matthew J.} and Mandigo, {Amy C.} and Nicolas Gordon and Fangjin Huang and Sanchaika Gaur and {de Leeuw}, Ren{\'e}e and Zhao, {Shuang G.} and Joseph Evans and Sumin Han and Theodore Parsons and Ruth Birbe and Peter McCue and Christopher McNair and Chand, {Saswati N.} and Ylenia Cendon-Florez and Peter Gallagher and McCann, {Jennifer J.} and {Poudel Neupane}, Neermala and Shafi, {Ayesha A.} and Emanuela Dylgjeri and Brand, {Lucas J.} and Tapio Visakorpi and Raj, {Ganesh V.} and Lallas, {Costas D.} and Trabulsi, {Edouard J.} and Gomella, {Leonard G.} and Dicker, {Adam P.} and Kelly, {Wm Kevin} and Leiby, {Benjamin E.} and Beatrice Knudsen and Feng, {Felix Y.} and Knudsen, {Karen E.}",
note = "Funding Information: We gratefully thank all the members of the Knudsen laboratory for their intellectual and technical support. Additionally, we thank the following institutions that supported this work: the NIH/NCI grants to KEK (R01 CA176401, R01 CA182569, R01 CA217329, P30 CA056036) and the Sidney Kimmel Cancer Center (5P30CA056036), the Prostate Cancer Foundation (to MJS and KEK), and the Translational Pathology and MetaOmics core facilities at SKCC. Publisher Copyright: {\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2018",
month = dec,
doi = "10.15252/emmm.201708816",
language = "English (US)",
volume = "10",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "12",
}