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PARPâ 1 regulates DNA repair factor availability
dc.contributor.authorSchiewer, Matthew J
dc.contributor.authorMandigo, Amy C
dc.contributor.authorGordon, Nicolas
dc.contributor.authorHuang, Fangjin
dc.contributor.authorGaur, Sanchaika
dc.contributor.authorLeeuw, Renée
dc.contributor.authorZhao, Shuang G
dc.contributor.authorEvans, Joseph
dc.contributor.authorHan, Sumin
dc.contributor.authorParsons, Theodore
dc.contributor.authorBirbe, Ruth
dc.contributor.authorMcCue, Peter
dc.contributor.authorMcNair, Christopher
dc.contributor.authorChand, Saswati N
dc.contributor.authorCendon‐florez, Ylenia
dc.contributor.authorGallagher, Peter
dc.contributor.authorMcCann, Jennifer J
dc.contributor.authorPoudel Neupane, Neermala
dc.contributor.authorShafi, Ayesha A
dc.contributor.authorDylgjeri, Emanuela
dc.contributor.authorBrand, Lucas J
dc.contributor.authorVisakorpi, Tapio
dc.contributor.authorRaj, Ganesh V
dc.contributor.authorLallas, Costas D
dc.contributor.authorTrabulsi, Edouard J
dc.contributor.authorGomella, Leonard G
dc.contributor.authorDicker, Adam P
dc.contributor.authorKelly, Wm. Kevin
dc.contributor.authorLeiby, Benjamin E
dc.contributor.authorKnudsen, Beatrice
dc.contributor.authorFeng, Felix Y
dc.contributor.authorKnudsen, Karen E
dc.date.accessioned2019-01-15T20:28:42Z
dc.date.available2020-02-03T20:18:24Zen
dc.date.issued2018-12
dc.identifier.citationSchiewer, 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; Cendon‐florez, 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 (2018). "PARPâ 1 regulates DNA repair factor availability." EMBO Molecular Medicine 10(12): n/a-n/a.
dc.identifier.issn1757-4676
dc.identifier.issn1757-4684
dc.identifier.urihttps://hdl.handle.net/2027.42/147045
dc.description.abstractPARPâ 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 PARPâ 1 enzymatic activity. Further investigation of the PARPâ 1â regulated transcriptome and secondary strategies for assessing PARPâ 1 activity in patient tissues revealed that PARPâ 1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA doubleâ strand breaks, suggesting that enhanced PARPâ 1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARPâ 1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1â mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARPâ 1 inhibition reduced HR factor availability and thus acted to induce or enhance â BRCAâ nessâ . These observations bring new understanding of PARPâ 1 function in cancer and have significant ramifications on predicting PARPâ 1 inhibitor function in the clinical setting.SynopsisBy integrating data generated in model systems and human tissues, and in silico analyses of cancer patientâ derived data, this study reveals that PARPâ 1 affects the expression of DNA repair factors through E2F1. Coâ targeting PARPâ 1 and the cell cycle machinery could be a novel treatment strategy.PARPâ 1 enzymatic and transcriptional regulatory functions are elevated as a function of prostate cancer (PCa) progression.PARPâ 1 impacts the transcriptional activity of E2F1, including regulation of cell cycle and DDR gene expression.HR factors are frequently transcriptionally deregulated in PCa, which is enriched in PCa progression.Transcriptional regulation of DNA repair factor expression by PARPâ 1 impacts the response to PARPi.By integrating data generated in model systems and human tissues, and in silico analyses of cancer patientâ derived data, this study reveals that PARPâ 1 affects the expression of DNA repair factors through E2F1. Coâ targeting PARPâ 1 and the cell cycle machinery could be a novel treatment strategy.
dc.publisherWiley Periodicals, Inc.
dc.subject.otherE2F1
dc.subject.otherPARP
dc.subject.othertranscription
dc.subject.otherDNA repair
dc.titlePARPâ 1 regulates DNA repair factor availability
dc.typeArticleen_US
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelMolecular, Cellular and Developmental Biology
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/147045/1/emmm201708816-sup-0001-Appendix.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/147045/2/emmm201708816.reviewer_comments.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/147045/3/emmm201708816.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/147045/4/emmm201708816-sup-0004-SDataFig5.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/147045/5/emmm201708816_am.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/147045/6/emmm201708816-sup-0003-SDataFig1.pdf
dc.identifier.doi10.15252/emmm.201708816
dc.identifier.sourceEMBO Molecular Medicine
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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