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

Abstract

Loss of WRN 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 hydroxyurea. 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.

WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

“…It has been reported that apoptosis-associated genes are dysfunctional in mice lacking Wrn protein 54 . In the meantime, we found more γH2AX signals appeared in wrn zebrafish at early developmental stage, indicating the loss of wrn caused DNA damage, which could be one of the plausible explanations that why loss of wrn caused apoptosis 55 . Microinjection of human WRN mRNA into the one-cell stage of wrn −/− mutant embryos could facilitate chondrocyte proliferation and increase total body length, indicating that WRN is crucial for chondrocyte growth development.…”

Protein Degradation Pathways Regulate the Functions of Helicases in the DNA Damage Response and Maintenance of Genomic Stability

“…Cells expressing a WRN variant that is mutated at the six lysine residues thereby blocking its acetylation are hypersensitive to MMC, suggesting that an important aspect of WRN’s role in the DNA damage response is its regulation by acetylation which prevents its proteolytic degradation via a ubiquitin-proteasome pathway. Thus WRN acetylation and deacetylation may serve as a switch during DNA damage conditions that influences WRN catalytic function or its own degradation which in turn alters its role at stalled replication forks or sites of DNA damage [ 69 ]. In the future, it will be valuable to assess if certain histone deacetylase (HDAC) inhibitors currently used in the clinic might affect the acetyltransferase that modifies WRN as it is known that this class of compounds can alter the acetylation state and function of non-histone proteins as well as their traditional histone targets [ 70 , 71 , 72 ].…”

Acetylation of BLM protein regulates its function in response to DNA damage

“…Acetylation modication plays a key role in the regulation of DNA repair and acts on many DNA repair related proteins. [39][40][41] SIRT1 is identied as one of the major deacetylases to catalyze this process. For example, SIRT1 deacetylated WRN at 6 lysine residues, promoting its translocation from nucleoli to the damage foci when DNA was impaired by cytotoxic substances, thus inhibiting its degradation.…”