Open AccessPARP‐1 regulates DNA repair factor availability
Author(s) -
Schiewer Matthew J,
Mandigo Amy C,
Gordon Nicolas,
Huang Fangjin,
Gaur Sanchaika,
Leeuw Renée,
Zhao Shuang G,
Evans Joseph,
Han Sumin,
Parsons Theodore,
Birbe Ruth,
McCue Peter,
McNair Christopher,
Chand Saswati N,
CendonFlorez Ylenia,
Gallagher Peter,
McCann Jennifer J,
Poudel Neupane Neermala,
Shafi Ayesha A,
Dylgjeri Emanuela,
Brand Lucas J,
Visakorpi Tapio,
Raj Ganesh V,
Lallas Costas D,
Trabulsi Edouard J,
Gomella Leonard G,
Dicker Adam P,
Kelly Wm. Kevin,
Leiby Benjamin E,
Knudsen Beatrice,
Feng Felix Y,
Knudsen Karen E
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708816
Subject(s) - library science , gerontology , cancer , medicine , computer science
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.