Poly [ADP-ribose] polymerase 1–Histone PARylation factor 1 complex (PARP1–HPF1) (PARP1–HPF1)

The Poly [ADP-ribose] polymerase 1–Histone PARylation factor 1 (PARP1–HPF1) complex is the fundamental catalytic unit responsible for initiating the DNA damage response through serine ADP-ribosylation (Gibbs-Seymour et al., 2016, PubMed 27658933). PARP1 (UniProt P09874) serves as a molecular sensor for DNA breaks, while HPF1 (UniProt Q9NWY4) acts as an essential cofactor that modulates PARP1's substrate specificity. Together, they form a joint active site that attaches ADP-ribose polymers to serine residues on histones and other DNA-binding proteins, facilitating chromatin remodeling and the recruitment of repair machinery (Suskiewicz et al., 2020, PubMed 32246145). This pathway is vital for maintaining genomic stability, and its dysregulation is a hallmark of various malignancies, particularly those with homologous recombination deficiencies (Lord & Ashworth, 2017, PubMed 28592531). Therapeutically, the PARP1–HPF1 complex is the target of PARP inhibitors (PARPi) such as Olaparib and Niraparib, which are used to treat cancers with BRCA1/2 mutations (FDA, 2014). These inhibitors work by competing with NAD+ at the catalytic site and by trapping the PARP1–HPF1 complex on DNA, which leads to lethal double-strand breaks during replication (Murai et al., 2012, PubMed 23118988). Understanding the interaction between PARP1 and HPF1 has been pivotal in explaining the mechanism of clinical PARP inhibitors and identifying potential resistance mechanisms in cancer therapy.

Other names

PARP1-HPF1 complexSerine ADP-ribosylation complexHPF1-PARP1PARP1-HPF1 heterodimerPoly-ADP-ribosylation pathway

Competitive inhibition of the NAD+ binding site on PARP1 and trapping of the PARP1–HPF1 complex on damaged DNA, leading to the accumulation of double-strand breaks and synthetic lethality in cells with deficient homologous recombination repair.