Poly [ADP-ribose] polymerase 1–Bromodomain-containing protein 4 protein–protein interface (PARP1–BRD4 PPI)

The Poly [ADP-ribose] polymerase 1–Bromodomain-containing protein 4 (PARP1–BRD4) protein–protein interface is a critical regulatory junction that links DNA damage response mechanisms with epigenetic transcriptional control. PARP1 is an enzyme essential for detecting DNA damage and facilitating repair [UniProt P09874], while BRD4 is a bromodomain and extra-terminal (BET) family protein that reads acetylated histones to promote gene expression [UniProt O60885]. Research has established that these two proteins physically interact to form a complex that drives the progression of aggressive cancers, particularly castration-resistant prostate cancer, by co-activating the transcription of oncogenes such as MYC and the androgen receptor [Kar et al., 2017, Nature Communications]. This interaction allows PARP1 to act as a scaffold or co-regulator that recruits BRD4 to specific genomic sites, enhancing the survival and proliferation of malignant cells. Therapeutic strategies targeting this interface include the development of dual-action inhibitors that bind to both the PARP1 catalytic site and BRD4 bromodomains, as well as small molecules designed to specifically disrupt the physical binding between the two proteins [Sun et al., 2021, J. Med. Chem.]. By simultaneously impairing DNA repair and suppressing oncogenic transcription, targeting the PARP1–BRD4 interface offers a synergistic approach to overcoming resistance to conventional monotherapies in oncology.

Other names

PARP1-BRD4 interactionPARP1-BRD4 complexPARP1-BET interactionPARP1-BRD4 functional axis

The mechanism involves the disruption of the physical association between PARP1 and BRD4, which prevents the recruitment of BRD4 to chromatin and inhibits the transcriptional activation of oncogenic drivers like MYC, while simultaneously blocking PARP1-dependent DNA repair pathways [Kar et al., 2017, Nature Communications; Sun et al., 2021, J. Med. Chem.].