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PARP2

Official Full Name
poly(ADP-ribose) polymerase 2
Organism
Homo sapiens
GeneID
10038
Background
This gene encodes poly(ADP-ribosyl)transferase-like 2 protein, which contains a catalytic domain and is capable of catalyzing a poly(ADP-ribosyl)ation reaction. This protein has a catalytic domain which is homologous to that of poly (ADP-ribosyl) transferase, but lacks an N-terminal DNA binding domain which activates the C-terminal catalytic domain of poly (ADP-ribosyl) transferase. The basic residues within the N-terminal region of this protein may bear potential DNA-binding properties, and may be involved in the nuclear and/or nucleolar targeting of the protein. Two alternatively spliced transcript variants encoding distinct isoforms have been found. [provided by RefSeq, Jul 2008]
Synonyms
ARTD2; ADPRT2; PARP-2; ADPRTL2; ADPRTL3; pADPRT-2;
Bio Chemical Class
Glycosyltransferases
Protein Sequence
MAARRRRSTGGGRARALNESKRVNNGNTAPEDSSPAKKTRRCQRQESKKMPVAGGKANKDRTEDKQDGMPGRSWASKRVSESVKALLLKGKAPVDPECTAKVGKAHVYCEGNDVYDVMLNQTNLQFNNNKYYLIQLLEDDAQRNFSVWMRWGRVGKMGQHSLVACSGNLNKAKEIFQKKFLDKTKNNWEDREKFEKVPGKYDMLQMDYATNTQDEEETKKEESLKSPLKPESQLDLRVQELIKLICNVQAMEEMMMEMKYNTKKAPLGKLTVAQIKAGYQSLKKIEDCIRAGQHGRALMEACNEFYTRIPHDFGLRTPPLIRTQKELSEKIQLLEALGDIEIAIKLVKTELQSPEHPLDQHYRNLHCALRPLDHESYEFKVISQYLQSTHAPTHSDYTMTLLDLFEVEKDGEKEAFREDLHNRMLLWHGSRMSNWVGILSHGLRIAPPEAPITGYMFGKGIYFADMSSKSANYCFASRLKNTGLLLLSEVALGQCNELLEANPKAEGLLQGKHSTKGLGKMAPSSAHFVTLNGSTVPLGPASDTGILNPDGYTLNYNEYIVYNPNQVRMRYLLKVQFNFLQLW
Open
Disease
Ovarian cancer, Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
3 +
Discontinued Drug
0

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Detailed Information

The PARP2 (Poly(ADP-ribose) Polymerase 2) gene is located on chromosome 14q11.2 and encodes a nuclear protein composed of 583 amino acids. It belongs to the poly(ADP-ribose) polymerase (PARP) family. Structurally, PARP2 contains a conserved catalytic domain that mediates ADP-ribosylation reactions but lacks the N-terminal DNA-binding domain found in its homolog PARP1. This structural distinction enables functional specialization.

PARP2 initiates DNA repair by recognizing strand breaks. Upon DNA damage, its catalytic domain utilizes NAD⁺ as a substrate to add poly(ADP-ribose) (PAR) chains to glutamate, aspartate, or serine residues of target proteins such as histones and DNA repair factors. These branched polymers, typically 20–30 units long, are synthesized in complex with the HPF1 protein, which confers specificity for serine ADP-ribosylation. Moreover, PARP2 can directly ADP-ribosylate the 5'-phosphate termini of DNA breaks, thereby stabilizing repair complexes. HPF1 not only defines substrate specificity but also limits the length of PAR chains to prevent excessive modification that would deplete cellular energy stores.

Figure 1. The domain structure of PARP2. (Szántó M, et al., 2024)

Physiological and Pathological Significance

Within the DNA repair network, PARP2 cooperates with PARP1 to regulate homologous recombination repair (HRR) and base excision repair (BER). Loss of PARP2 function markedly increases cellular sensitivity to DNA double-strand breaks, especially in the context of BRCA1/2 deficiencies. This phenomenon, known as "synthetic lethality," underpins the rationale for targeting PARP2 in cancer therapy.

However, excessive PARP2 activation is also implicated in pathological processes. Under chronic inflammation or oxidative stress, sustained activation leads to NAD⁺ depletion, ATP exhaustion, and caspase-independent cell death. These effects contribute to neurodegenerative diseases such as Parkinson's disease and ischemia-reperfusion injury.

In oncology, aberrant PARP2 expression is associated with various cancers:

  • Ovarian and Breast Cancer: In BRCA1/2-mutant tumors, PARP2 is upregulated as a compensatory mechanism to maintain genomic stability. However, its overexpression can also confer resistance to PARP inhibitors.
  • Prostate Cancer: In metastatic castration-resistant prostate cancer (mCRPC), PARP2 promotes tumor progression by regulating androgen receptor stability, particularly in BRCA-mutant subtypes.
  • Endometrial Cancer: In homologous recombination-deficient (HRD-positive) patients, PARP2-mediated repair pathway activation is linked to chemotherapy resistance but may also present a window for targeted intervention.

Clinical Applications and Challenges

The "synthetic lethality" strategy has led to the development of PARP inhibitors (PARPi), with olaparib being the first approved agent. Its clinical use has expanded across multiple cancer types:

  • Ovarian Cancer: The SOLO-1 trial demonstrated that olaparib as first-line maintenance therapy in BRCA-mutant advanced ovarian cancer achieved a median progression-free survival (PFS) of 56.0 months, extending 42.2 months beyond the placebo group. In 2023, the NMPA approved olaparib in combination with bevacizumab for HRD-positive patients based on the DUO-E study, where the median PFS in the combination group was 37.2 months versus 17.7 months in the control group.
  • Prostate Cancer: The PROpel trial showed that olaparib combined with abiraterone in BRCA-mutant mCRPC patients resulted in an unreached radiographic PFS (rPFS), compared to 8 months in the control group. In May 2023, the FDA approved this combination for BRCA-mutant patients. However, the benefit in non-mutated subgroups was limited.
  • Breast Cancer: Patients with PALB2-mutated breast cancer, representing 1%–2% of hereditary breast cancer cases, showed strong responses to olaparib, with an objective response rate (ORR) of 82%, comparable to BRCA-mutated cases.

Table: Key Clinical Applications and Efficacy of PARP Inhibitors

IndicationTreatment RegimenTarget PopulationKey Clinical Endpoint
First-line ovarian maintenanceOlaparib monotherapyBRCA mutationMedian PFS: 56.0 months (vs. 13.8 months)
HRD+ ovarian maintenanceOlaparib + BevacizumabHRD-positiveMedian PFS: 37.2 months (vs. 17.7 months)
First-line mCRPCOlaparib + AbirateroneBRCA mutationrPFS not reached (vs. 8 months)
Metastatic breast cancerOlaparib monotherapyPALB2 mutationORR: 82%

Despite encouraging outcomes, PARPi faces three major clinical challenges:

  • Resistance Mechanisms: These include PARP2 gene amplification, reactivation of the HRR pathway, and increased expression of drug efflux pumps such as ABCG2.
  • Hematologic Toxicity: Olaparib is associated with grade ≥3 anemia in 25% of patients and thrombocytopenia in 20%, often requiring dose modifications.
  • Market Dynamics: Domestic PARPi agents face limitations in indications and competition from generics, with sales reaching only one-sixth of imported counterparts, highlighting the strategic bottleneck of "me-too" drugs.

Future Directions

Innovative approaches in PARP2-targeted therapy focus on combination strategies and next-generation inhibitors:

  • Combination with Immunotherapy: In the DUO-E study, olaparib combined with the PD-L1 inhibitor durvalumab reduced the risk of disease progression by 50% in advanced endometrial cancer, suggesting potential in reshaping the tumor immune microenvironment.
  • Dual-Target Inhibitors: Johnson & Johnson is developing a combination tablet of niraparib and abiraterone acetate to simultaneously target PARP and androgen synthesis in BRCA-mutant mCRPC. This formulation has been submitted to the FDA.
  • Catalytic-Specific Inhibitors: Novel compounds such as AZD5305 selectively inhibit PARP2's ability to generate branched PAR chains without affecting PARP1, potentially reducing bone marrow suppression. These agents are currently in Phase II clinical trials.

References:

  1. Zhang H, Zha S. The dynamics and regulation of PARP1 and PARP2 in response to DNA damage and during replication. DNA Repair (Amst). 2024 Aug;140:103690.
  2. Szántó M, Yélamos J, Bai P. Specific and shared biological functions of PARP2 - is PARP2 really a lil' brother of PARP1? Expert Rev Mol Med. 2024 May 3;26:e13.
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