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EMBO Mol Med. 2018 Dec;10(12). pii: e8816. doi: 10.15252/emmm.201708816.

PARP-1 regulates DNA repair factor availability.

Author information

1
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA karen.knudsen@jefferson.edu.
2
Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA.
3
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
4
Cedars-Sinai Medical Center, Los Angeles, CA, USA.
5
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
6
Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA.
7
Cooper University Health, Camden, NJ, USA.
8
University of Tampere, Tampere, Finland.
9
UT Southwestern, Dallas, TX, USA.
10
Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA.
11
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
12
Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
13
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
14
Departments of Radiation Oncology, Urology, and Medicine, University of California, San Francisco, San Francisco, CA, USA.

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:

DNA repair; E2F1; PARP; transcription

PMID:
30467127
PMCID:
PMC6284389
DOI:
10.15252/emmm.201708816
[Indexed for MEDLINE]
Free PMC Article

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