Two is better: roles of the PARP1/HPF1 complex in DNA damage repair

Our DNA is fragile and subjected to numerous stresses, both endogenous and exogenous. The lesions suffered by the DNA are thus part of the life of a cell and can be at the origin of numerous pathologies, notably cancers. This is why it is essential for our cells to preserve the integrity of their genome via specialized and efficient DNA repair mechanisms. Among the different repair players, PARP1 is responsible for detecting lesions and signaling their presence to subsequent players capable of correcting them to return to healthy DNA. PARP1 leaves marks, consisting of ADP-ribose chains, on proteins located in the immediate vicinity of the damage. These marks are recognized by repair proteins and also serve to decondense the DNA near the lesions to make them more accessible.

Recent studies have shown that, contrary to what had long been assumed, PARP1 does not function alone and requires a co-factor, called HPF1. In two collaborative projects with laboratories led by Ivan Matic at the Max Planck Institute for Biology of Aging (Cologne, Germany), Roderick O'Sullivan at the University of Pittsburg (USA), Gyula Timinszky at the University of Szeged (Hungary), Haico Van Attikum at the University of Leiden (The Netherlands), and Ivan Ahel at the University of Oxford (United Kingdom), the SPARTE team of the IGDR sought to clarify the contribution of HPF1 to the repair process.

By combining fluorescence microscopy approaches on living cells with the development of antibodies specific to ADP-ribose markers, the work carried out showed that HPF1 controls not only the location where ADP-ribose chains are attached, but also their number and length. In particular, these observations highlight for the first time the existence of a specific signal that would not be constituted by ADP-ribose polymers but by monomers. While the signal constituted by poly-ADP-ribose marks is very transient after the induction of DNA damage, the signal associated with mono-ADP-ribose marks persists over much longer periods. Using mass spectrometry approaches, the researchers further showed that mono-ADP-ribose marks were specifically recognized by certain repair factors such as the RNF114 protein, suggesting that signaling via mono-ADP-ribose may play a different role than that via poly-ADP-ribose.

Because of its role in regulating the balance between poly- and mono-ADP-ribose, the HPF1 protein has also been shown to be essential for the process of local DNA decondensation, which is necessary to facilitate access to damaged DNA for repair proteins. Without this cofactor, PARP1 is no longer able to play its damage-signaling role properly and many repair proteins are therefore no longer efficiently recruited to the latter. This ultimately leads to a loss of repair efficiency and early cell death in the presence of DNA damage-inducing stress. Thus, the work carried out, recently published in the journals Molecular Cell and Nature Structural and Molecular Biology, describes how the PARP1/HPF1 complex contributes to preserve our genome from external aggressions.