Poly(ADP-Ribose) Links the DNA Damage Response and Biomineralization

Abstract

Summary: Biomineralization of the extracellular matrix is an essential, regulated process. Inappropriate mineralization of bone and the vasculature has devastating effects on patient health, yet an integrated understanding of the chemical and cell biological processes that lead to mineral nucleation remains elusive. Here, we report that biomineralization of bone and the vasculature is associated with extracellular poly(ADP-ribose) synthesized by poly(ADP-ribose) polymerases in response to oxidative and/or DNA damage. We use ultrastructural methods to show poly(ADP-ribose) can form both calcified spherical particles, reminiscent of those found in vascular calcification, and biomimetically calcified collagen fibrils similar to bone. Importantly, inhibition of poly(ADP-ribose) biosynthesis in vitro and in vivo inhibits biomineralization, suggesting a therapeutic route for the treatment of vascular calcifications. We conclude that poly(ADP-ribose) plays a central chemical role in both pathological and physiological extracellular matrix calcification. : Müller et al. investigate the physicochemical process of extracellular matrix calcification in both physiological (bone) and pathological (vascular calcification) contexts. They find that oxidative stress-induced poly(ADP-ribose) nucleates calcium phosphate mineral crystals on extracellular matrix substrates and that calcification is inhibited by poly(ADP-ribose) polymerase (PARP) enzyme inhibitors. Keywords: poly(ADP-ribose), vascular smooth muscle cell, bone, DNA damage