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Review Research Published OnlineFirst June 10, 2014; DOI: 10.1158/1541-7786.MCR-13-0672 Molecular Cancer Review Research Transcriptional Roles of PARP1 in Cancer Matthew J. Schiewer1,2 and Karen E. Knudsen1,2,3,4 Abstract þ Poly (ADP-ribose) polymerase-1 (PARP1) is an abundant, ubiquitously expressed NAD -dependent nuclear enzyme that has prognostic value for a multitude of human cancers. PARP1 activity serves to poly (ADP-ribose)- ylate the vast majority of known client proteins and affects a number of cellular and biologic outcomes, by mediating the DNA damage response (DDR), base-excision repair (BER), and DNA strand break (DSB) pathways. PARP1 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-deficient model systems. Strikingly, recent studies have unearthed exciting new transcriptional-regulatory roles for PARP1, which has profound implications for human malignancies and will be reviewed herein. Mol Cancer Res; 12(8); 1069–80. Ó2014 AACR. Introduction Regulation of PARylation Poly (ADP-ribose) polymerase-1 (PARP1) is an enzyme PARP1 is a DNA-dependent ADP-ribosyl transferase that responsible for approximately 90% of the ADP-ribosyl is localized in the nucleus and is frequently associated with transferase activity [poly (ADP-ribose)ylation (PARylation)] chromatin (1, 2, 12). The capacity of PARP1 to associate in both nontransformed and malignant human cells (1), the with DNA is manifested via direct binding and/or interacting majority of which is self-directed (1, 2). The PARP family of with nucleosomes and other chromatin-associated proteins, enzymes contains 18 family members, PARP1 being the first including transcription factors (13), the transcriptional to be characterized (3), which PARylate client proteins using machinery (14, 15), and chromatin modifiers (1, 2, 12). The þ NAD as a cofactor, and thereby control a diverse set of enzymatic activity of PARP1 is regulated by what it is bound biologic functions (4). The first defined role for PARP1 was to, such as damaged DNA or other nuclear proteins to orchestrate DNA damage resolution, especially in the (1, 12, 16–21), as well as posttranslational modifications, context of base excision repair (BER; ref. 5). However, such as autoPARylation (inhibitory; refs. 22–26) and phos- subsequent studies implicated PARP1 as harboring pleio- phorylation by ERK1/2 (activating, DNA independent; þ tropic cellular functions, including DNA repair/mainte- refs. 27, 28). In addition, an NAD synthase [nicotinamide nance of genomic integrity, DNA methylation, regulation mononucleotide adenylyltransferase-1 (NMNAT-1)] associ- of circadian clocks, chromatin regulation, and histone mod- ates with PARP1, thus allowing for a proximal source of þ ification (2, 6–8). Parp-1-deficient mouse models are viable NAD cofactor and increasing PARP1 activity (ref. 29; and demonstrate increased sensitivity to genotoxic stress, Fig. 1A). resistance to DNA damage–induced cell death, increased The first identified roles of PARP1 were associated with tumorigenesis in chemically or genetically induced models DNA damage and genomic maintenance, with specific roles (reviewed in ref. 2) and altered hypoxic response (9). Cell in BER, single-strand (SSB), and double-strand break (DSB) models of Parp1 deficiency demonstrate altered transcrip- repair (5). In response to DNA damage, PARP1 enzymatic tion of p53 targets (ref. 10; heat shock factor 1; ref. 11). Most function is activated, and persists in a correlative manner recently, means by which PARP1 regulates gene transcrip- with the extent of the damage. When DNA breaks are tion have been identified (2, 6, 7, 12); the present review repairable, PARP1 regulates repair and cell survival; but in addresses the function and consequence of PARP1-regulated response to catastrophic damage, PARP1 regulates the transcription in the context of human malignancies. induction of cell death (30–32). In addition to playing roles in SSB and DSB repair (33–35), PARP1 has been implicated in homologous recombination (HR) at stalled or collapsed Authors' Affiliations: 1Kimmel Cancer Center, Departments of 2Cancer replication forks (36, 37), as well as regulating nonhomol- Biology, 3Urology, and 4Radiation Oncology, Thomas Jefferson University, – Philadelphia, Pennsylvania ogous end-joining (NHEJ; refs. 38 41). Whereas the PARP family of enzymes is responsible for PAR anabolism, the PAR Corresponding Author: Karen E. Knudsen, Thomas Jefferson University, Kimmel Cancer Center, 233 S. 10th St., Bluemle Building - Room 908, glycohydrolases (PARG) regulate PAR catabolism. PAR Philadelphia, PA 19107. Phone: 215-503-8574; Fax: 215-503-8573; E-mail: hydrolysis is regulated by a number of isoforms of the single [email protected] PARG gene that arise from splicing. The long isoforms of doi: 10.1158/1541-7786.MCR-13-0672 PARG shuttle between the cytosol and the nucleus, whereas Ó2014 American Association for Cancer Research. the short isoform is exclusively cytoplasmic (42–45). www.aacrjournals.org 1069 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst June 10, 2014; DOI: 10.1158/1541-7786.MCR-13-0672 Schiewer and Knudsen Figure 1. A, Poly (ADP-ribose) polymerase-1 (PARP1) enzymatic activity is activated by multiple stimuli, including: DNA damage, nicotinamide adenine dinucleotide (NADþ), proximal NADþ produced by Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1), which interacts with PARP1, and phosphoryltion by ERK1/2. The majority of PARP1 enzymatic activity is self-directed, as depicted by the Poly (ADP-ribose) chains (PAR), and hyper-PARylated PARP1 inhibits PARP1 enzymatic activity, as depicted by the squared line. PAR moities are cleaved by Poly (ADP-ribose) glycohydrase (PARG) members. B, Enzymatically active PARP1 stimulates (blue arrows) or inhibits (blocked red line) the recuritment and downstream DNA damage repair functions of multiple DNA repair factors as depicted. SSB, single strand break. HR, homologous recombination. NHEJ, Non-homologous end joining. Although the PARP superfamily and PARG play clearly of tumor suppressor and oncogene function, (ii) regulation important and distinct roles in PAR metabolism, the role of of effectors of the metastatic process, (iii) regulation of cell PARG/PARP1 interplay in cancer remains poorly described. survival and adaptation, and (iv) transcriptional regulation in In addition, PAR catalysis in the mitochondria has been hormone-dependent cancers. discovered to be performed by ADP-ribosylhydrolase 3 (ARH3), not PARG, for which very little is known in the Basic Mechanisms of PARP1-Mediated context of cancer (46–48). Current understanding of PARP1-driven PARylation is Transcriptional Control that in response to stimuli (such as DNA damage; Fig. 1B), Although initially characterized as a factor intimately PARP1 enzymatic function is robustly and rapidly induced, involved in regulation of DNA repair/genomic mainte- þ using NAD as the donor for ADP-ribose resulting in nance, PARP1 was recently demonstrated to exert pleiotro- pic roles in transcriptional regulation in cancer and multiple biologic outcomes, and PAR is degraded by PARG þ to ADP-ribose monomers. These terminal ADP-ribose noncancer model systems (2, 6, 7, 12). Under NAD - monomers are then removed by the recently discovered depleted conditions, PARP1 compacts chromatin by bind- TARG1, whose deficiency results in neurodegenerative ing to and bringing together nucleosomes and can also affect disease (49). PAR moieties generated can noncovalently chromatin structure through PARylation of histones, thus interact with multiple domains that result in controlling of disrupting nucleosomes and resultant chromatin architec- multiple pathways (reviewed in refs. 46, 50). In addition, ture (1, 24, 54–56). PARP1 has also been found to localize to recent proteomics work has begun to define the PARylated promoters of actively transcribed genes and prevent binding proteome upon various stimuli and how these PARylated of Histone H1, thus promoting transcriptionally active proteins are often involved in chromatin organization and chromatin (57). The transcriptional regulatory functions of transcriptional regulation, as well as the DNA damage PARP1 are multi-fold, do not universally require enzymatic response (DDR; ref. 51–53). Here, the major transcriptional activity, and are manifest through divergent functions, regulatory functions of PARP1, and the downstream bio- including enhancer binding, association with insulators, logic consequence(s) of these events for human malignancies modulation of chromatin structure, and/or direct transcrip- are discussed. Specific areas of focus address (i) modulation tion factor regulation (as either a context-dependent 1070 Mol Cancer Res; 12(8) August 2014 Molecular Cancer Research Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst June 10, 2014; DOI: 10.1158/1541-7786.MCR-13-0672 PARP1, Transcription, and Cancer coactivator or corepressor). PARP1 binding at regulatory loci at these loci. These data correlate PARP1 to the insulating of genes does not always correlate with activation of tran- capacity of CTCF. scription. In fact, PARP1 binding can sometimes correlate In addition to chromatin-remodeling factors and insula- with transcriptional repression (2,
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