PARP-1 regulates DNA repair factor availability

被引：52

作者：

Schiewer, Matthew J. ^{[1
,2
]}

Mandigo, Amy C. ^{[1
,2
]}

Gordon, Nicolas ^{[1
,2
]}

Huang, Fangjin ^{[3
]}

Gaur, Sanchaika ^{[3
]}

de Leeuw, Renee ^{[1
,2
]}

Zhao, Shuang G. ^{[4
]}

Evans, Joseph ^{[4
]}

Han, Sumin ^{[4
]}

Parsons, Theodore ^{[2
,5
]}

Birbe, Ruth ^{[6
]}

McCue, Peter ^{[2
,5
]}

McNair, Christopher ^{[1
,2
]}

Chand, Saswati N. ^{[1
,2
]}

Cendon-Florez, Ylenia ^{[1
,2
]}

Gallagher, Peter ^{[1
,2
]}

McCann, Jennifer J. ^{[1
,2
]}

Neupane, Neermala Poudel ^{[1
,2
]}

Shafi, Ayesha A. ^{[1
,2
]}

Dylgjeri, Emanuela ^{[1
,2
]}

Brand, Lucas J. ^{[1
,2
]}

Visakorpi, Tapio ^{[7
]}

Raj, Ganesh V. ^{[8
]}

Lallas, Costas D. ^{[2
,9
]}

Trabulsi, Edouard J. ^{[2
,9
]}

Gomella, Leonard G. ^{[2
,9
]}

Dicker, Adam P. ^{[2
,10
]}

Kelly, Wm. Kevin ^{[2
,11
]}

Leiby, Benjamin E. ^{[2
,12
]}

Knudsen, Beatrice ^{[3
]}

Feng, Felix Y. ^{[13
,14
,15
]}

Knudsen, Karen E. ^{[1
,2
,9
,10
,11
]}

机构：

[1] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA

[2] Thomas Jefferson Univ, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA

[3] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA

[4] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA

[5] Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA

[6] Cooper Univ Hlth, Camden, NJ USA

[7] Univ Tampere, Tampere, Finland

[8] UT Southwestern, Dallas, TX USA

[9] Thomas Jefferson Univ, Dept Urol, Philadelphia, PA 19107 USA

[10] Thomas Jefferson Univ, Dept Radiat Oncol, Philadelphia, PA 19107 USA

[11] Thomas Jefferson Univ, Dept Med Oncol, Philadelphia, PA 19107 USA

[12] Thomas Jefferson Univ, Dept Pharmacol & Expt Therapeut, Philadelphia, PA 19107 USA

[13] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA USA

[14] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA

[15] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

来源：

EMBO MOLECULAR MEDICINE | 2018年 / 10卷 / 12期

关键词：

DNA repair; E2F1; PARP; transcription; CELL-FREE DNA; EPITHELIAL OVARIAN-CANCER; BRCA2 REVERSION MUTATIONS; EX-VIVO CULTURE; PROSTATE-CANCER; POLY(ADP-RIBOSE) POLYMERASE; GENE-EXPRESSION; BREAST-CANCER; HOMOLOGOUS RECOMBINATION; RIBOSE POLYMERASE;

D O I：

10.15252/emmm.201708816

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：20

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