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PARP1

Official Full Name
poly (ADP-ribose) polymerase 1
Background
This gene encodes a chromatin-associated enzyme, poly(ADP-ribosyl)transferase, which modifies various nuclear proteins by poly(ADP-ribosyl)ation. The modification is dependent on DNA and is involved in the regulation of various important cellular processes such as differentiation, proliferation, and tumor transformation and also in the regulation of the molecular events involved in the recovery of cell from DNA damage. In addition, this enzyme may be the site of mutation in Fanconi anemia, and may participate in the pathophysiology of type I diabetes. [provided by RefSeq, Jul 2008]
Synonyms
PARP1; poly (ADP-ribose) polymerase 1; PARP; PPOL; ADPRT; ARTD1; ADPRT1; PARP-1; ADPRT 1; pADPRT-1; poly [ADP-ribose] polymerase 1; poly(ADP-ribose) polymerase; poly(ADP-ribose) synthetase; poly[ADP-ribose] synthase 1; poly(ADP-ribosyl)transferase; ADP-ribosyltransferase NAD(+); NAD(+) ADP-ribosyltransferase 1; poly (ADP-ribose) polymerase family, member 1; ADP-ribosyltransferase diphtheria toxin-like 1; ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase); poly[ADP-ribose] synthetase 1; wu:fc60f12; zgc:110092; si:dkey-206f10.3

Poly (ADP-ribose) polymerase-1 (PARP1) is an enzyme responsible for approximately 90% of the ADP-ribosyl transferase activity [poly (ADP-ribose)ylation (PARylation)] in both nontransformed and malignant human cells, the majority of which is self-directed. PARP1 is localized in the nucleus and is frequently associated with chromatin. The capacity of PARP1 to associate with DNA is manifested via direct binding and/or interacting with nucleosomes and other chromatin-associated proteins, including transcription factors, the transcriptional machinery, and chromatin modifiers.

PARP1 function and regulation

PARP1 is the first to be identified among a family of 17 proteins which cleaves NAD+ for the ADP ribosylation of protein acceptors, generating nicotinamide as a by-product. The large 113kDa nuclear protein usually has a low intrinsic enzymatic activity that may be significantly enhanced by binding both ssDB and dsDB through either of its N-terminal zinc fingers, bringing about conformational changes via its third zinc finger to increase catalytic activity at the C-terminal. Because large amounts of negative charges are conferred by adding extensive polymers of ADP-ribose (PAR), PARP1 modulates the activity of its substrates, including itself, to control several important cellular functions such as DNA methylation, DNA damage repair, chromatin regulation, regulation of circadian clocks, transcriptional regulation and cell death. However, PAR is short-lived and as soon as its purpose is served, it is rapidly degraded within minutes of synthesis by the exoglycosidic and endoglycosidic activities of poly (ADP-ribose) glycohydrase (PARG) or PAR hydrolase (ARH).

PARP1 function and regulation. Figure 1. PARP1 function and regulation.

Modulation of tumor suppressor and oncogene function by PARP1

Complementing the transcriptional and chromatin-regulatory functions of PARP1, PARP1 also directly modulates sequence-specific transcription factors, including several of high relevance for human malignancies. Notably, PARP1 is in transcriptional-repressive complexes with p53, and PARylation of p53 within in this context results in recruitment of HDAC1 and HDAC2. This transcriptional-repressor complex blocks the expression of metastasis-associated protein 1 (MTA1), which is involved in nucleosome remodeling and transcriptional repression, is frequently enriched in many cancers, and is associated with disease progression and metastasis. Abrogation of PARP1-dependent MTA1 repression results in elevated levels of hypoxia-inducible factor (HIF)1a and VEGF, suggesting that PARP1-mediated p53 transcriptional function negatively regulates MTA1 expression and cancer associated genes and phenotypes. As such, in addition to maintaining genomic integrity, part of the tumor-suppressive roles for both p53 and PARP1 may include regulation of MTA1. Other studies have implicated a functional interaction between PARP1 and p53 in multiple biologic functions. Specifically, it has been identified that PARP1 regulates the p53-mediated DDR via stabilization of p53 in response to radiation, and PARP inhibition suppresses the activation of p53 in response to radiation. PARP1 activation results in ATP depletion and subsequently reduced TAF1 kinase activity and p21 activation. Parp1–null mouse embryonic fibroblasts (MEF) have approximately 2X lower basal p53 expression and DNA damage–dependent reduction than wild-type MEFs, and functional PARP1 is required for p53- dependent cytotoxicity in response to proteasome inhibitors.

The functions of PARP inhibitors in cancer therapy

PARP1 plays key roles in multiple DNA damage response pathways and thus maintains genome integrity. Notably, most of PARP1’s functions are dependent on its PARylation ability, which renders the latter a potential target for tumor therapy. The development of PARP inhibitors originated from the observation that nicotinamide, a product of PARP catalytic activity, is a weak PARP inhibitor. So far, multiple PARP inhibitors have been identified and exhibit promising anticancer potential. In general, the clinical development of PARP inhibitors follows two distinct strategies based on the molecular status of a cancer cell. First, PARP1 inhibitors may find potential use in chemosensitization in combination therapies. Second, PARP inhibitors may be useful as a single agent in killing tumors in HR-deficient patients based on synthetic lethality, which means that blocking the functions of two gene products simultaneously can cause cell death, while blocking either one is nonlethal. Many cancer therapies utilize DNA-damaging agents to kill tumor cells, which often triggers DNA repair and renders the cancer cells resistant to the therapies. Considering that PARP1 plays essential roles in multiple DNA repair pathways, it is expected that blocking PARP will sensitize tumors to chemotherapy or radiotherapy, thereby improving the therapeutic index of such approaches.

References:

  1. Ko H L, Ren E C. Functional aspects of PARP1 in DNA repair and transcription. Biomolecules, 2012, 2(4): 524-548.
  2. Xu S, et al. Poly (ADP‐ribose) polymerase 1 (PARP1) in atherosclerosis: from molecular mechanisms to therapeutic implications. Medicinal research reviews, 2014, 34(3): 644-675.
  3. Chaudhuri A R, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nature reviews Molecular cell biology, 2017, 18(10): 610.
  4. Schiewer M J, Knudsen K E. Transcriptional roles of PARP1 in cancer. Molecular Cancer Research, 2014, 12(8): 1069-1080.
  5. Wang Z, et al. The role of PARP1 in the DNA damage response and its application in tumor therapy. Frontiers of medicine, 2012, 6(2): 156-164.

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