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.
| Original language | English (US) |
|---|---|
| Article number | e8816 |
| Journal | EMBO Molecular Medicine |
| Volume | 10 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2018 |
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Keywords
- DNA repair
- E2F1
- PARP
- transcription
ASJC Scopus subject areas
- Molecular Medicine
Cite this
PARP-1 regulates DNA repair factor availability. / Schiewer, Matthew J.; Mandigo, Amy C.; Gordon, Nicolas; Huang, Fangjin; Gaur, Sanchaika; de Leeuw, Renée; Zhao, Shuang G.; Evans, Joseph; Han, Sumin; Parsons, Theodore; Birbe, Ruth; McCue, Peter; McNair, Christopher; Chand, Saswati N.; Cendon-Florez, Ylenia; Gallagher, Peter; McCann, Jennifer J.; Poudel Neupane, Neermala; Shafi, Ayesha A.; Dylgjeri, Emanuela; Brand, Lucas J.; Visakorpi, Tapio; Raj, Ganesh; 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.
In: EMBO Molecular Medicine, Vol. 10, No. 12, e8816, 01.12.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PARP-1 regulates DNA repair factor availability
AU - Schiewer, Matthew J.
AU - Mandigo, Amy C.
AU - Gordon, Nicolas
AU - Huang, Fangjin
AU - Gaur, Sanchaika
AU - de Leeuw, Renée
AU - Zhao, Shuang G.
AU - Evans, Joseph
AU - Han, Sumin
AU - Parsons, Theodore
AU - Birbe, Ruth
AU - McCue, Peter
AU - McNair, Christopher
AU - Chand, Saswati N.
AU - Cendon-Florez, Ylenia
AU - Gallagher, Peter
AU - McCann, Jennifer J.
AU - Poudel Neupane, Neermala
AU - Shafi, Ayesha A.
AU - Dylgjeri, Emanuela
AU - Brand, Lucas J.
AU - Visakorpi, Tapio
AU - Raj, Ganesh
AU - Lallas, Costas D.
AU - Trabulsi, Edouard J.
AU - Gomella, Leonard G.
AU - Dicker, Adam P.
AU - Kelly, Wm Kevin
AU - Leiby, Benjamin E.
AU - Knudsen, Beatrice
AU - Feng, Felix Y.
AU - Knudsen, Karen E.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
KW - DNA repair
KW - E2F1
KW - PARP
KW - transcription
UR - http://www.scopus.com/inward/record.url?scp=85058006502&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058006502&partnerID=8YFLogxK
U2 - 10.15252/emmm.201708816
DO - 10.15252/emmm.201708816
M3 - Article
C2 - 30467127
AN - SCOPUS:85058006502
VL - 10
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 12
M1 - e8816
ER -