Poly(ADP-ribose) polymerases (PARPs) are a group of NAD+-dependent enzymes that play essential roles in DNA damage recognition and repair.
In humans, 17 PARP enzymes have been identified, among which PARP1 is the predominant catalytic enzyme, accounting for more than 90% of poly(ADP-ribosyl)ation activity associated with DNA repair.
PARPs preserve genomic stability by sensing DNA lesions and recruiting repair factors, functioning in coordination with key tumor suppressors such as BRCA1 and BRCA2.
Figure 1: Mechanism of PARP-mediated DNA Repair
I. Core Mechanisms and Biological Functions
DNA Repair Deficiency
Loss-of-function in PARP1/2 compromises single-strand break (SSB) repair. In BRCA1/2 mutant cells, this triggers synthetic lethality.
Therapeutic Vulnerability
HR-deficient tumors show marked sensitivity to PARP inhibitors (e.g., Olaparib), though they may resist platinum-based agents.
•PARP1: The principal sensor for SSBs; catalyzes PARylation to recruit repair complexes.
•PARP2 & PARP3: Auxiliary regulators contributing to Base Excision Repair (BER).
•Other PARPs (5 & 7): Involved in apoptosis, transcription, and cellular stress responses.
II. Clinical Relevance
Pharmacological inhibition of PARP enzymatic activity exploits synthetic lethality to selectively eliminate BRCA-mutated tumor cells. These inhibitors are now essential in treating ovarian and breast cancers.
Implications for Immunotherapy: Emerging studies suggest PARP1 activity modulates DNA damage tolerance in T lymphocytes, potentially influencing anti-tumor immune responses.
III. Recent Research Advances
Third-generation PARP Inhibitors
Structure-guided design using high-resolution co-crystal structures has led to inhibitors with superior potency and isoform selectivity.
Emerging Molecular Targets
Discovery of the PARP2–FOXO1 interaction in prostate cancer provides a new rationale for isoform-selective therapies.
By teamBiofargo
BIOFARGO TEAM
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