Poly [ADP-ribose] polymerase 7 (PARP7), also known as TCDD-inducible poly-ADP-ribose polymerase (TIPARP), is an enzyme of the PARP family that catalyzes the transfer of ADP-ribose from NAD+ to specific amino acids of itself and other substrateproteins.[1] It is encoded by the TIPARPgene on chromosome 3.[2][3] The 17 members of the PARP family are divided into polyPARPs, monoPARPs, and PARPs without catalytic activity according to different catalytic functions.[4] TIPARP is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. TIPARP is involved in tumor generation and immune function recovery.[5]
TIPARP is characterized by a sequence consisting of 657 amino acids.[6] The protein contains a CCCH-type zinc finger domain for DNA/RNA binding, a protein−protein interaction domain mediating iso-ADP-ribose interaction, a conserved ADP-ribosyltransferase catalytic domain with ADP-ribosyl transferase activity, and an N-terminal nuclear localization signal (NLS).[7]
Functions of TIPARP
TIPARP acts by adding a single unit of ADP-ribose to TANK-binding kinase 1 (TBK1), which prevents its activation and represses the type I Interferon (IFN-I) response.[8] TIPARP is amplified in many cancers and acts as a "brake" in the type I IFN response to cytosolic nucleic acid. TIPARP is involved in various biological processes, including intrinsic immunity, cell division, response to viral infections, transcription regulation, receptor degradation, and nervous system development.[9]
Role in viral infection
TIPARP plays a dual role in viral replication, with its specific function depending on the type of virus. Following infection with coronavirus, upregulation of TIPARP expression influences the host's antiviral response.[citation needed] Modulating the expression and activity of TIPARP to strengthen the host's immune response represents a promising novel antiviral strategy. TIPARP modulates the antiviral activity of PARP13, an inactive member of the PARP family[clarification needed] and plays a role in inhibiting the replication of a wide range of RNA viruses, through mono-ADP-ribosylation (MARylation) modification.[10] Conversely, high expression levels of TIPARP inhibits the replication of specific viruses such as Venezuelan equine encephalitis virus, Getah virus, Sindbis virus, and other RNA viruses.[9]
Role in tumor
Activation of the signaling pathway for IFN-I release is an effective way for the human body to clear tumor cells. In the IFN-I signaling pathway, the activation of TBK1 is essential for signal transduction. TIPARP inhibits TBK1 activation via mono-ADP-ribosylation, resulting in the disruption of the IFN-I pathway, ultimately contributing to immune escape in tumor cells.[11] Inhibition of TIPARP activity restores TBK1 phosphorylation function and activates the IFN-I signaling pathway. This cascade activates the Janus kinase (JAK)signal transducer and activator of transcription pathway, promoting the upregulation of CXCL10 expression and recruiting cytotoxic T cells to eliminate tumor cells.[9]
TIPARP inhibits the IFN-I signaling pathway by blocking the degradation of FRA1. Reducing the expression level of TIPARP promotes the degradation of FRA1 and restores the IFN-1 signaling. TIPARP inhibitors have clinical potential in treating FRA1-driven cancers, offering a new application strategy of TIPARP inhibitors for cancer therapy.[12]
The upregulation of PD-1/PD-L1 immune checkpoints obstructs the IFN-I signaling pathway, thereby impeding the recruitment of cytotoxic T lymphocytes. TIPARP inhibitors in combination with PD1/PD-L1 immune checkpoint inhibitor (ICIs) improve tumor prognosis and provide synergistic anti-tumor effects.[13]
Application in cancer treatment
The expression of TIPARP varies across different tumor types, and its role differs accordingly. Down-regulating the expression level of TIPARP has excellent therapeutic effects on a variety of cancers, so that the use of TIPARP inhibitors is widely used as a novel approach to immune-mediated anti-tumor therapy.[12]
In ovarian cancer, reducing the expression of TIPARP increases microtubule stability and slows the growth of ovarian cancer cells. Knocking TIPARP gene leads to a decrease in cell growth and an increase in microtubule content [14]. In prostate cancer, the activation of the Androgen Receptor (AR) signaling is important for tumor cell survival and growth.[15] TIPARP modifies multiple cysteine residues of AR through ADP-ribosylation, thereby promoting the growth and survival of prostate cancer cells. The inhibition of TIPARP prevents AR from forming complexes with DTX3L and PARP9, limiting the growth and survival of prostate cancer cells.[9]
Ribon Therapeutics reported the first TIPARP inhibitor, RBN-2397. This compound has progressed to clinical phase II trials for the treatment of advanced and metastatic solid tumors. RBN-2397 exhibits extremely high inhibitory potency against TIPARP with an IC50 value of 5.0M and significant growth inhibition of CT-26 tumor cells in a mouse xenograft model.[16]
Role in other physiological functions
Overactivation of astrocytes exacerbates brain damage and impairs the recovery of brain function following a stroke. The expression of TIPARP activates autophagy and stimulates astrocyte activation.[17] By inhibiting TIPARP expression, the activation of astrocytes can be reduced, thereby positively influencing stroke treatment. TIPARP expression impacts hepatic energy metabolism and inflammatory response by decreasing NAD+ levels, consequently affecting glucose regulation and promoting the development of nonalcoholic fatty liver disease. TIPARP is also associated with blood pressure, oral cancer, uveal melanoma, meningioma, bone, and obesity diseases.[9]
↑ Katoh M, Katoh M (Jul 2003). "Identification and characterization of human TIPARP gene within the CCNL amplicon at human chromosome 3q25.31". Int J Oncol. 23 (2): 541–7. doi:10.3892/ijo.23.2.541. PMID12851707.
↑ Lu, Alvin Z.; Abo, Ryan; Ren, Yue; Gui, Bin; Mo, Jan-Rung; Blackwell, Danielle; Wigle, Tim; Keilhack, Heike; Niepel, Mario (2019). "Enabling drug discovery for the PARP protein family through the detection of mono-ADP-ribosylation". Biochemical Pharmacology. 167: 97–106. doi:10.1016/j.bcp.2019.05.007. PMID31075269.
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