Acetylation of Werner syndrome protein (WRN): relationships with DNA damage, DNA replication and DNA metabolic activities.

[werner syndrome]

Loss of Werner syndrome protein function causes Werner syndrome , characterized by increased genomic instability , elevated cancer susceptibility and premature aging . Although WRN is subject to acetylation , phosphorylation and sumoylation , the impact of these modifications on WRN 's DNA metabolic function remains unclear . Here , we examined in further depth the relationship between WRN acetylation and its role in DNA metabolism , particularly in response to induced DNA damage . Our results demonstrate that endogenous WRN is acetylated somewhat under unperturbed conditions . However , levels of acetylated WRN significantly increase after treatment with certain DNA damaging agents or the replication inhibitor HU . Use of DNA repair-deficient cells or repair pathway inhibitors further increase levels of acetylated WRN , indicating that induced DNA lesions and their persistence are at least partly responsible for increased acetylation . Notably , acetylation of WRN correlates with inhibition of DNA synthesis , suggesting that replication blockage might underlie this effect . Moreover , WRN acetylation modulates its affinity for and activity on certain DNA structures , in a manner that may enhance its relative specificity for physiological substrates . Our results also show that acetylation and deacetylation of endogenous WRN is a dynamic process , with sirtuins and other histone deacetylases contributing to WRN deacetylation . These findings advance our understanding of the dynamics of WRN acetylation under unperturbed conditions and following DNA damage induction , linking this modification not only to DNA damage persistence but also potentially to replication stalling caused by specific DNA lesions . Our results are consistent with proposed metabolic roles for WRN and genomic instability phenotypes associated with WRN deficiency .

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Diseases presenting "relative specificity" symptom

werner syndrome

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