聚ADP核糖聚合酶
PARP抑制剂
DNA修复
转录因子
DNA损伤
生物
癌症研究
染色质
背景(考古学)
转录组
细胞生物学
DNA
遗传学
基因
基因表达
聚合酶
古生物学
作者
Matthew J. Schiewer,Amy C. Mandigo,Nicolas Gordon,Christopher McNair,Costas D. Lallas,Edouard J. Trabulsi,Benjamin E. Leiby,Karen E. Knudsen
标识
DOI:10.1200/jco.2019.37.7_suppl.269
摘要
269 Background: PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Previously, it was determined that PARP-1 ins involved in regulation of androgen receptor activity. Methods: Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity.Results: 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”. Conclusions: 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.
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