EMBO Molecular Medicine (Nov 2018)
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 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
Affiliations
- Matthew J Schiewer
- Department of Cancer Biology, Thomas Jefferson University
- Amy C Mandigo
- Department of Cancer Biology, Thomas Jefferson University
- Nicolas Gordon
- Department of Cancer Biology, Thomas Jefferson University
- Fangjin Huang
- Cedars‐Sinai Medical Center
- Sanchaika Gaur
- Cedars‐Sinai Medical Center
- Renée de Leeuw
- Department of Cancer Biology, Thomas Jefferson University
- Shuang G Zhao
- Department of Radiation Oncology, University of Michigan
- Joseph Evans
- Department of Radiation Oncology, University of Michigan
- Sumin Han
- Department of Radiation Oncology, University of Michigan
- Theodore Parsons
- Sidney Kimmel Cancer Center, Thomas Jefferson University
- Ruth Birbe
- Cooper University Health
- Peter McCue
- Sidney Kimmel Cancer Center, Thomas Jefferson University
- Christopher McNair
- Department of Cancer Biology, Thomas Jefferson University
- Saswati N Chand
- Department of Cancer Biology, Thomas Jefferson University
- Ylenia Cendon‐Florez
- Department of Cancer Biology, Thomas Jefferson University
- Peter Gallagher
- Department of Cancer Biology, Thomas Jefferson University
- Jennifer J McCann
- Department of Cancer Biology, Thomas Jefferson University
- Neermala Poudel Neupane
- Department of Cancer Biology, Thomas Jefferson University
- Ayesha A Shafi
- Department of Cancer Biology, Thomas Jefferson University
- Emanuela Dylgjeri
- Department of Cancer Biology, Thomas Jefferson University
- Lucas J Brand
- Department of Cancer Biology, Thomas Jefferson University
- Tapio Visakorpi
- University of Tampere
- Ganesh V Raj
- UT Southwestern
- Costas D Lallas
- Sidney Kimmel Cancer Center, Thomas Jefferson University
- Edouard J Trabulsi
- Sidney Kimmel Cancer Center, Thomas Jefferson University
- Leonard G Gomella
- Sidney Kimmel Cancer Center, Thomas Jefferson University
- Adam P Dicker
- Sidney Kimmel Cancer Center, Thomas Jefferson University
- Wm. Kevin Kelly
- Sidney Kimmel Cancer Center, Thomas Jefferson University
- Benjamin E Leiby
- Sidney Kimmel Cancer Center, Thomas Jefferson University
- Beatrice Knudsen
- Cedars‐Sinai Medical Center
- Felix Y Feng
- Departments of Radiation Oncology, Urology, and Medicine, University of California, San Francisco
- Karen E Knudsen
- Department of Cancer Biology, Thomas Jefferson University
- DOI
- https://doi.org/10.15252/emmm.201708816
- Journal volume & issue
-
Vol. 10,
no. 12
pp. 1 – 20
Abstract
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
