Histone PARylation factor 1: a review of its role in the DNA damage response

Although poly-(ADP ribose) polymerase 1 (PARP1) and PARylation of histones have been known for over 50 years and have been successfully targeted by anti-cancer drugs, we are just coming up to the 10-year anniversary of the paradigm-shifting discovery of histone PARylation factor 1 (HPF1), the protein that facilitates the modification of histones by PARP1. In addition to forming a shared active site with PARP1 by contributing a catalytic residue, HPF1 dramatically changes the activity of PARP1 both in vitro and in vivo with respect to substrate choice, PAR chain length, sites of modification, and consequent effects on chromatin. In this review, we summarize the current knowledge status in the PARP1-HPF1 field, with an emphasis on the many open questions that the PARP research community still needs to resolve. A better understanding of this intriguing enzyme system will enable ongoing efforts to develop a more complete understanding of the response to DNA damage and better inhibitors of PARP1.