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