Site-specific noncovalent interaction of the biopolymer poly(ADP-ribose) with the Werner syndrome protein regulates protein functions.

[werner syndrome]

Werner syndrome is a premature aging disorder that is caused by defects in the Werner protein (WRN ). WRN is a member of the RecQ helicase family and possesses helicase and exonuclease activities . It is involved in various aspects of DNA metabolism such as DNA repair , telomere maintenance , and replication . Poly (ADP-ribose ) polymerase 1 (PARP 1 ) is also involved in these processes by catalyzing the formation of the nucleic-acid-like biopolymer poly (ADP-ribose ) (PAR ). It was previously shown that WRN interacts with PARP 1 and that WRN activity is inhibited by PARP 1 . Using several bioanalytical approaches , here we demonstrate that the enzymatic product of PARP 1 , i .e ., PAR , directly interacts with WRN physically and functionally . First , WRN binds HPLC-size-fractionated short and long PAR in a noncovalent manner . Second , we identified and characterized a PAR-binding motif (PBM ) within the WRN sequence and showed that several basic and hydrophobic amino acids are of critical importance for mediating the PAR binding . Third , PAR-binding inhibits the DNA-binding , the helicase and the exonuclease activities of WRN in a concentration-dependent manner . On the basis of our results we propose that the transient nature of PAR produced by living cells would provide a versatile and swiftly reacting control system for WRN 's function . More generally , our work underscores the important role of noncovalent PAR-protein interactions as a regulatory mechanism of protein function .

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werner syndrome

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