PARP7

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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 substrate proteins.[1] It is encoded by the TIPARP gene 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] PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. PARP7 is involved in tumor generation and immune function recovery.[5]

Structure of PARP7

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PARP7 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 PARP7

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PARP7 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] PARP7 is amplified in many cancers and acts as a "brake" in the type I IFN response to cytosolic nucleic acid. PARP7 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

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PARP7 plays a dual role in viral replication, with its specific function depending on the type of virus. Following infection with coronavirus, upregulation of PARP7 expression influences the host's antiviral response.[citation needed] Modulating the expression and activity of PARP7 to strengthen the host's immune response represents a promising novel antiviral strategy. PARP7 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 PARP7 inhibits the replication of specific viruses such as Venezuelan equine encephalitis virus, Getah virus, Sindbis virus, and other RNA viruses.[9]

Role in tumor

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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. PARP7 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 PARP7 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]

PARP7 inhibits the IFN-I signaling pathway by blocking the degradation of FRA1. Reducing the expression level of PARP7 promotes the degradation of FRA1 and restores the IFN-1 signaling. PARP7 inhibitors have clinical potential in treating FRA1-driven cancers, offering a new application strategy of PARP7 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. PARP7 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

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The expression of PARP7 varies across different tumor types, and its role differs accordingly. Down-regulating the expression level of PARP7 has excellent therapeutic effects on a variety of cancers, so that the use of PARP7 inhibitors is widely used as a novel approach to immune-mediated anti-tumor therapy.[12]

In ovarian cancer, reducing the expression of PARP7 increases microtubule stability and slows the growth of ovarian cancer cells. Knockdown of the PARP7 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] PARP7 modifies multiple cysteine residues of AR through ADP-ribosylation, thereby promoting the growth and survival of prostate cancer cells. The inhibition of PARP7 prevents AR from forming complexes with DTX3L and PARP9, limiting the growth and survival of prostate cancer cells.[9]

Ribon Therapeutics reported the first PARP7 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 PARP7 with an IC50 value of 5.0 M and significant growth inhibition of CT-26 tumor cells in a mouse xenograft model.[16]

Role in other physiological functions

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Overactivation of astrocytes exacerbates brain damage and impairs the recovery of brain function following a stroke. The expression of PARP7 activates autophagy and stimulates astrocyte activation.[17] By inhibiting PARP7 expression, the activation of astrocytes can be reduced, thereby positively influencing stroke treatment. PARP7 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. PARP7 is also associated with blood pressure, oral cancer, uveal melanoma, meningioma, bone, and obesity diseases.[9]

References

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  1. ^ Hassa, Paul, O. (2008). "The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases". Frontiers in Bioscience. 13 (13): 3046–3082. doi:10.2741/2909. ISSN 1093-9946. PMID 17981777.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ 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. PMID 12851707.
  3. ^ "Entrez Gene: TIPARP TCDD-inducible poly(ADP-ribose) polymerase".
  4. ^ 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. PMID 31075269.
  5. ^ Vyas, Sejal; Chesarone-Cataldo, Melissa; Todorova, Tanya; Huang, Yun-Han; Chang, Paul (2013-08-06). "A systematic analysis of the PARP protein family identifies new functions critical for cell physiology". Nature Communications. 4 (1) 2240. Bibcode:2013NatCo...4.2240V. doi:10.1038/ncomms3240. ISSN 2041-1723. PMC 3756671. PMID 23917125.
  6. ^ Damale, Manoj G.; Pathan, Shahebaaz K.; Shinde, Devanand B.; Patil, Rajendra H.; Arote, Rohidas B.; Sangshetti, Jaiprakash N. (December 2020). "Insights of tankyrases: A novel target for drug discovery". European Journal of Medicinal Chemistry. 207 112712. doi:10.1016/j.ejmech.2020.112712. ISSN 0223-5234. PMID 32877803.
  7. ^ C. Alarcon de la Lastra; Villegas, I.; Sanchez-Fidalgo, S. (2007-03-01). "Poly(ADP-Ribose) Polymerase Inhibitors: New Pharmacological Functions and Potential Clinical Implications". Current Pharmaceutical Design. 13 (9): 933–962. doi:10.2174/138161207780414241. ISSN 1381-6128. PMID 17430191.
  8. ^ Yamada, Taisho; Horimoto, Hiromasa; Kameyama, Takeshi; Hayakawa, Sumio; Yamato, Hiroaki; Dazai, Masayoshi; Takada, Ayato; Kida, Hiroshi; Bott, Debbie; Zhou, Angela C; Hutin, David; Watts, Tania H; Asaka, Masahiro; Matthews, Jason; Takaoka, Akinori (2016-04-18). "Constitutive aryl hydrocarbon receptor signaling constrains type I interferon–mediated antiviral innate defense". Nature Immunology. 17 (6): 687–694. doi:10.1038/ni.3422. ISSN 1529-2908. PMID 27089381.
  9. ^ a b c d e Qiu, Feihuang; Wang, Jianqiao; Huang, Kehan; Shang, Tianxiang; Wang, Chenghao; Yan, Wenxin; Xu, Yungen; Gu, Hongfeng (2025-09-25). "PARP7: an Emerging Therapeutic Target-Insights into Biological Functions and Advances in Small-Molecule Inhibitor Development". Journal of Medicinal Chemistry. 68 (19): 19846–19870. doi:10.1021/acs.jmedchem.5c01335. ISSN 0022-2623. PMID 40994152.
  10. ^ Rodriguez, Kelsie M; Buch-Larsen, Sara C; Kirby, Ilsa T; Siordia, Ivan Rodriguez; Hutin, David; Rasmussen, Marit; Grant, Denis M; David, Larry L; Matthews, Jason; Nielsen, Michael L; Cohen, Michael S (2020-12-30). "Author response: Chemical genetics and proteome-wide site mapping reveal cysteine MARylation by PARP-7 on immune-relevant protein targets". Biochemistry and Chemical Biology. doi:10.7554/elife.60480.sa2.
  11. ^ Jeltema, Devon; Knox, Kennady; Dobbs, Nicole; Tang, Zhen; Xing, Cong; Araskiewicz, Antonina; Yang, Kun; Siordia, Ivan Rodriguez; Matthews, Jason; Cohen, Michael; Yan, Nan (2025-02-19). "PARP7 inhibits type I interferon signaling to prevent autoimmunity and lung disease". Journal of Experimental Medicine. 222 (5) e20241184. doi:10.1084/jem.20241184. ISSN 0022-1007. PMC 11837972. PMID 39969510.
  12. ^ a b Popova, Katerina; Benedum, Johannes; Engl, Magdalena; Lütgendorf-Caucig, Carola; Fossati, Piero; Widder, Joachim; Podar, Klaus; Slade, Dea (2025-03-24). "PARP7 as a new target for activating anti-tumor immunity in cancer". EMBO Molecular Medicine. 17 (5): 872–888. doi:10.1038/s44321-025-00214-6. ISSN 1757-4684. PMC 12081928. PMID 40128585.
  13. ^ Manetsch, Patrick; Hottiger, Michael O. (2024-11-06). "Unleashing viral mimicry: A combinatorial strategy to enhance the efficacy of PARP7 inhibitors". BioEssays. 47 (2) 2400087. doi:10.1002/bies.202400087. ISSN 0265-9247. PMC 11755700. PMID 39502005.
  14. ^ Palavalli Parsons, Lavanya H; Challa, Sridevi; Gibson, Bryan A; Nandu, Tulip; Stokes, MiKayla S; Huang, Dan; Lea, Jayanthi S; Kraus, W Lee (2020-12-24). "Identification of PARP-7 substrates reveals a role for MARylation in microtubule control in ovarian cancer cells". Biochemistry and Chemical Biology. doi:10.7554/elife.60481.sa2.
  15. ^ Siddique, Hifzur Rahman; Mishra, Shrawan Kumar; Karnes, R. Jeffery; Saleem, Mohammad (2011-08-14). "Lupeol, a Novel Androgen Receptor Inhibitor: Implications in Prostate Cancer Therapy". Clinical Cancer Research. 17 (16): 5379–5391. doi:10.1158/1078-0432.ccr-11-0916. ISSN 1078-0432. PMC 4573593. PMID 21712449.
  16. ^ Gu, Hongfeng; Yan, Wenxin; Wang, Yong; Xu, Wenbo; Huang, Lei; Yang, Jieping; Zhai, Bingxin; Wang, Hong; Su, Yupei; Zhu, Qihua; Liu, Beibei; Hao, Haiping; Zou, Yi; Xu, Yungen (2022-12-28). "Discovery of the Potent and Highly Selective PARP7 Inhibitor as a Novel Immunotherapeutic Agent for Tumors". Journal of Medicinal Chemistry. 66 (1): 473–490. doi:10.1021/acs.jmedchem.2c01452. ISSN 0022-2623. PMID 36576395.
  17. ^ Han, Bing; Zhang, Yuan; Zhang, Yanhong; Bai, Ying; Chen, Xufeng; Huang, Rongrong; Wu, Fangfang; Leng, Shuo; Chao, Jie; Zhang, John H.; Hu, Gang; Yao, Honghong (2018-07-03). "Novel insight into circular RNA HECTD1 in astrocyte activation via autophagy by targeting MIR142-TIPARP: implications for cerebral ischemic stroke". Autophagy. 14 (7): 1164–1184. doi:10.1080/15548627.2018.1458173. ISSN 1554-8627. PMC 6103660. PMID 29938598.

Further reading

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