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

doi:10.15252/emmm.201708816

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 DylgjeriLucas 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

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

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	https://doi.org/10.15252/emmm.201708816
State	Published - Dec 2018

Keywords

DNA repair
E2F1
PARP
transcription

ASJC Scopus subject areas

Molecular Medicine

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Schiewer, M. J., Mandigo, A. C., Gordon, N., Huang, F., Gaur, S., de Leeuw, R., Zhao, S. G., Evans, J., Han, S., Parsons, T., Birbe, R., McCue, P., McNair, C., Chand, S. N., Cendon-Florez, Y., Gallagher, P., McCann, J. J., Poudel Neupane, N., Shafi, A. A., ... Knudsen, K. E. (2018). PARP-1 regulates DNA repair factor availability. EMBO Molecular Medicine, 10(12), Article e8816. https://doi.org/10.15252/emmm.201708816

Schiewer, MJ, Mandigo, AC, Gordon, N, Huang, F, Gaur, S, de Leeuw, R, Zhao, SG, Evans, J, Han, S, Parsons, T, Birbe, R, McCue, P, McNair, C, Chand, SN, Cendon-Florez, Y, Gallagher, P, McCann, JJ, Poudel Neupane, N, Shafi, AA, Dylgjeri, E, Brand, LJ, Visakorpi, T, Raj, GV, Lallas, CD, Trabulsi, EJ, Gomella, LG, Dicker, AP, Kelly, WK, Leiby, BE, Knudsen, B, Feng, FY & Knudsen, KE 2018, 'PARP-1 regulates DNA repair factor availability', EMBO Molecular Medicine, vol. 10, no. 12, e8816. https://doi.org/10.15252/emmm.201708816

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title = "PARP-1 regulates DNA repair factor availability",

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",

author = "Schiewer, {Matthew J.} and Mandigo, {Amy C.} and Nicolas Gordon and Fangjin Huang and Sanchaika Gaur and {de Leeuw}, Ren{\'e}e and Zhao, {Shuang G.} and Joseph Evans and Sumin Han and Theodore Parsons and Ruth Birbe and Peter McCue and Christopher McNair and Chand, {Saswati N.} and Ylenia Cendon-Florez and Peter Gallagher and McCann, {Jennifer J.} and {Poudel Neupane}, Neermala and Shafi, {Ayesha A.} and Emanuela Dylgjeri and Brand, {Lucas J.} and Tapio Visakorpi and Raj, {Ganesh V.} and Lallas, {Costas D.} and Trabulsi, {Edouard J.} and Gomella, {Leonard G.} and Dicker, {Adam P.} and Kelly, {Wm Kevin} and Leiby, {Benjamin E.} and Beatrice Knudsen and Feng, {Felix Y.} and Knudsen, {Karen E.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2018",

month = dec,

doi = "10.15252/emmm.201708816",

language = "English (US)",

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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 V.

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

Y1 - 2018/12

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

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JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 12

M1 - e8816

ER -

PARP-1 regulates DNA repair factor availability

Abstract

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ASJC Scopus subject areas

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