PARP-1 regulates DNA repair factor availability

Matthew J. Schiewer, Amy C. Mandigo, Nicolas Gordon, Fangjin Huang, Sanchaika Gaur, Renée de Leeuw, Shuang G. Zhao, Joseph Evans, Sumin Han, Theodore Parsons, Ruth Birbe, Peter McCue, Christopher McNair, Saswati N. Chand, Ylenia Cendon-Florez, Peter Gallagher, Jennifer J. McCann, Neermala Poudel Neupane, Ayesha A. Shafi, Emanuela DylgjeriLucas J. Brand, Tapio Visakorpi, Ganesh V. Raj, Costas D. Lallas, Edouard J. Trabulsi, Leonard G. Gomella, Adam P. Dicker, Wm Kevin Kelly, Benjamin E. Leiby, Beatrice Knudsen, Felix Y. Feng, Karen E. Knudsen

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Article numbere8816
JournalEMBO Molecular Medicine
Volume10
Issue number12
DOIs
StatePublished - Dec 2018

Keywords

  • DNA repair
  • E2F1
  • PARP
  • transcription

ASJC Scopus subject areas

  • Molecular Medicine

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