PARP‐1 regulates DNA repair factor availability

• Main Authors: Matthew J Schiewer, Amy C Mandigo, Nicolas Gordon, Fangjin Huang, Sanchaika Gaur, Renée deLeeuw, 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 Dylgjeri, Lucas 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
• Format: Article
• Language: English
• Published: Wiley 2018-12-01
• Series: EMBO Molecular Medicine
• Subjects: DNA repair; E2F1; PARP; transcription
• Online Access: https://doi.org/10.15252/emmm.201708816

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.