Poly(ADP-ribose) polymerase-1 regulates vimentin expression in lung cancer cells

Chu, Shijian; Xu, Honghao; Ferro, Thomas J.; Rivera, Paola

doi:10.1152/ajplung.00197.2007

Cited by 21 publications

(17 citation statements)

References 44 publications

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“…Reports indicate that PARP-1, itself, can interact with gene promoters (16)(17)(18), and so we asked whether PARP-1 could be detected at the BRCA1 promoter by ChIP. We were able to detect association of PARP-1 with the BRCA1 promoter in untreated A549 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130

Hegan¹,

Lü²,

Stachelek³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

186

111

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Inhibitors of poly(ADP-ribose) polymerase (PARP) are in clinical trials for cancer therapy, on the basis of the role of PARP in recruitment of base excision repair (BER) factors to sites of DNA damage. Here we show that PARP inhibition to block BER is toxic to hypoxic cancer cells, in which homology-dependent repair (HDR) is known to be down-regulated. However, we also report the unexpected finding that disruption of PARP, itself, either via chemical PARP inhibitors or siRNAs targeted to PARP-1, can inhibit HDR by suppressing expression of BRCA1 and RAD51, key factors in HDR of DNA breaks. Mechanistically, PARP inhibition was found to cause increased occupancy of the BRCA1 and RAD51 promoters by repressive E2F4/p130 complexes, a pathway prevented by expression of HPV E7, which disrupts p130 activity, or by siRNAs to knock down p130 expression. Functionally, disruption of p130 by E7 expression or by siRNA knockdown also reverses the cytotoxicity and radiosensitivity associated with PARP inhibition, suggesting that the down-regulation of BRCA1 and RAD51 is central to these effects. Direct measurement of HDR using a GFP-based assay demonstrates reduced HDR in cells treated with PARP inhibitors. This work identifies a mechanism by which PARP regulates DNA repair and suggests new strategies for combination cancer therapies.DNA repair | hypoxia P oly(ADP-ribose) polymerases (PARPs) comprise a family of enzymes that catalyze ADP ribosylation of a variety of cellular factors (1-4). PARP-1 is thought to play a key role in DNA repair, primarily by modifying chromatin factors at sites of DNA damage and thereby recruiting repair factors. Inhibitors of PARP have attracted interest for cancer therapy because cancer cells deficient in BRCA1 or BRCA2 due to inactivating mutations are sensitive to PARP inhibition (5-8). This has been attributed to the role of PARP in recruiting base excision repair (BER) factors that remove damaged bases and fix single-strand breaks (SSBs) (1). SSBs persisting into S-phase produce replication fork collapse, requiring BRCA1-and BRCA2-mediated homology-dependent repair (HDR) for resolution (5, 9, 10).In prior work, we found that hypoxia suppresses HDR in human cells via transcriptional down-regulation of BRCA1 and RAD51 (11-15). Hence, we hypothesized that cancer cells in hypoxia, with acquired deficiency in HDR, might have increased sensitivity to PARP inhibition. Work presented here confirms this hypothesis, showing that PARP inhibitors are more cytotoxic to hypoxic than to normoxic cells. Because hypoxia causes BRCA1 and RAD51 down-regulation by stimulating E2F4/p130 occupancy of the BRCA1 and RAD51 promoters, we asked whether disruption of p130 function via expression of human papillomavirus (HPV) E7 would reverse the sensitivity of hypoxic cells to PARP inhibition. We found that E7 expression, as predicted, does confer resistance to PARP inhibitors on hypoxic cells, but surprisingly, it also blocks the toxicity of PARP inhibition in normoxic cells.As a basis for this effect, we present eviden...

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Section: Resultsmentioning

confidence: 99%

Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130

Hegan¹,

Lü²,

Stachelek³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

186

111

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“…Interestingly, this transcriptional activation was independent of the enzymatic activity of PARP-1, and could be suppressed by H 2 O 2 , which is an activator of PARP-1 enzymatic function. H 2 O 2 treatment resulted in diminished PARP-1 protein expression as well as vimentin protein expression, and induced overexpression of PARP-1 resulted in greater H 2 O 2 -induced repression of vimentin promoter activity, suggesting that PARP-1 may play an active role in inhibition of vimentin expression(78). Although the study described here clearly implicates PARP-1 in the transcriptional regulation of vimentin, further study as to the biological consequence is needed.…”

Section: Regulation Of Effectors Of the Metastatic Process By Parp-1mentioning

confidence: 99%

Transcriptional Roles of PARP1 in Cancer

Schiewer

Knudsen

2014

Molecular Cancer Research

157

136

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Poly (ADP-ribose) polymerase-1 (PARP-1) is an abundant, ubiquitously expressed NAD+-dependent nuclear enzyme that has prognostic value for a multitude of human cancers. PARP-1 activity serves to poly (ADP-ribose)-ylate the vast majority of known client proteins and affects a number of cellular and biological outcomes, by mediating DNA damage response (DDR), base-excision repair (BER), and DNA strand break (DSB) pathways. PARP-1 is also critically important for the maintenance of genomic integrity, as well as chromatin dynamics and transcriptional regulation. Evidence also indicates that PARP-directed therapeutics are “synthetic lethal” in BRCA1/2-dieficient model systems. Strikingly, recent studies have unearthed exciting new transcriptional-regulatory roles for PARP-1, which has profound implications for human malignancies and will be reviewed herein.

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“…Transcriptional regulation by PARP1 involves both ADP-ribosylation-dependent and independent mechanisms (Figure 3). Furthermore, PARP1 exerts its effects on transcription both in a DNA sequence-dependent and independent manner, through motif recognition at specific gene promoters [24,25,26,27,30,115,116,117,118,119,120,121,122,123] and chromatin remodeling [20,22], respectively. …”

Section: Parp1 As a Transcriptional Regulator Controlling Expressimentioning

confidence: 99%

Functional Aspects of PARP1 in DNA Repair and Transcription

2012

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Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP-ribosylating enzyme essential for initiating various forms of DNA repair. Inhibiting its enzyme activity with small molecules thus achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers. Through enzyme-dependent chromatin remodeling and enzyme-independent motif recognition, PARP1 also plays important roles in regulating gene expression. Besides presenting current findings on how each process is individually controlled by PARP1, we shall discuss how transcription and DNA repair are so intricately linked that disturbance by PARP1 enzymatic inhibition, enzyme hyperactivation in diseases, and viral replication can favor one function while suppressing the other.

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Poly(ADP-ribose) polymerase-1 regulates vimentin expression in lung cancer cells

Cited by 21 publications

References 44 publications

Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130

Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130

Transcriptional Roles of PARP1 in Cancer

Functional Aspects of PARP1 in DNA Repair and Transcription

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