Abstract
Y-box-binding protein 1 (YB-1) is a multifunctional cellular factor overexpressed in tumors resistant to chemotherapy. An intrinsically disordered structure together with a high positive charge peculiar to YB-1 allows this protein to function in almost all cellular events related to nucleic acids including RNA, DNA and poly(ADP-ribose) (PAR). In the present study we show that YB-1 acts as a potent poly(ADP-ribose) polymerase 1 (PARP1) cofactor that can reduce the efficiency of PARP1 inhibitors. Similarly to that of histones or polyamines, stimulatory effect of YB-1 on the activity of PARP1 was significantly higher than the activator potential of Mg2+ and was independent of the presence of EDTA. The C-terminal domain of YB-1 proved to be indispensable for PARP1 stimulation. We also found that functional interactions of YB-1 and PARP1 can be mediated and regulated by poly(ADP-ribose).
Highlights
The long-lasting investigation of principles underlying DNA repair and its regulation has drawn the attention of researchers as a basis for the development of new approaches for cancer therapy
In the present study we show that Y-box-binding protein 1 (YB-1) acts as a potent poly(ADP-ribose) polymerase 1 (PARP1) cofactor that can reduce the efficiency of PARP1 inhibitors
It was shown earlier by fluorescence titration technique that YB-1 can physically interact with PARP1, and this interaction is not disrupted in the presence of damaged DNA [31]
Summary
The long-lasting investigation of principles underlying DNA repair and its regulation has drawn the attention of researchers as a basis for the development of new approaches for cancer therapy. One of the most promising targets in this respect is poly(ADP-ribose) polymerase 1 (PARP1), the key regulator of DNA repair events [2]. PARP1 transition from an inactive to active state occurs upon interaction with exposed bases at the site of DNA damage believed to induce restructuring of the protein auto-inhibitory domain [3]. Activated PARP1 synthesizes long (about 200–300 monomers) and branched chains of poly(ADP-ribose) (PAR) using NAD+ as a substrate [4]. The functions of PAR in DNA repair are extremely numerous. PARP1 had been recently shown to modify strand break termini suggesting the possible role of poly(ADP-ribose) in bridging broken DNA molecules similar to the role supposed for small non-coding RNAs [6,7,8]. Altmeyer and co-authors demonstrated that PAR nucleates non-membranous compartmentalization at sites of DNA damage [8]
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