Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks.

[werner syndrome]

WRN protein , defective in Werner syndrome (WS ), a human segmental progeria , is a target of serine /threonine kinases involved in sensing DNA damage . DNA-PK phosphorylates WRN in response to DNA double strand breaks (DSBs ). However , the main phosphorylation sites and functional importance of the phosphorylation of WRN has remained unclear . Here , we identify Ser-440 and -467 in WRN as major phosphorylation sites mediated by DNA-PK .In vitro , DNA-PK fails to phosphorylate a GST-WRN fragment with S 440 A and /or S 467 A substitution . In addition , full length WRN with the mutation expressed in 293 T cells was not phosphorylated in response to DSBs produced by bleomycin . Accumulation of the mutant WRN at the site of laser-induced DSBs occurred with the same kinetics as wild type WRN in live HeLa cells . While the wild type WRN relocalized to the nucleoli after 24 hours recovery from etoposide-induced DSBs , the mutant WRN remained mostly in the nucleoplasm . Consistent with this , WS cells expressing the mutants exhibited less DNA repair efficiency and more sensitivity to etoposide , compared to those expressing wild type . Our findings indicate that phosphorylation of Ser-440 and -467 in WRN are important for relocalization of WRN to nucleoli , and that it is required for efficient DSB repair .

Diseases
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Diseases presenting "double strand breaks" symptom

werner syndrome

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