title: Phosphorylation of the Cajal body protein WRAP53β by ATM promotes its involvement in the DNA damage response.
abstract: The cellular response to DNA double-strand breaks is orchestrated by the protein kinase ATM, which phosphorylates key actors in the DNA repair network. WRAP53β is a multifunctional protein that controls trafficking of factors to Cajal bodies, telomeres and DNA double-strand breaks but what regulates the involvement of WRAP53β in these separate processes remains unclear. Here, we show that in response to various types of DNA damage, including IR and UV, WRAP53β is phosphorylated on serine residue 64 by ATM with a time-course that parallels its accumulation at DNA lesions. Interestingly, recruitment of phosphorylated WRAP53β (pWRAP53βS64) to sites of such DNA damage promotes its interaction with γH2AX at these locations. Moreover, pWRAP53βS64stimulates the accumulation of the repair factor 53BP1 at DNA double-strand breaks and enhances repair of this type of damage via homologous recombination and non-homologous end joining. At the same time, phosphorylation of WRAP53β is dispensable for its localization to Cajal bodies, where it accumulates even in unstressed cells. These findings not only reveal ATM to be an upstream regulator of WRAP53β, but also indicates that phosphorylation of WRAP53β at serine 64 controls its involvement in the DNA damage response and may also restrict its other functions.
authors.affiliation: a Department of Oncology-Pathology , Cancer Centrum Karolinska (CCK), Karolinska Institutet , Stockholm , Sweden.
authors.forename: Christos
authors.initials: C
authors.lastname: Coucoravas
authors.affiliation: a Department of Oncology-Pathology , Cancer Centrum Karolinska (CCK), Karolinska Institutet , Stockholm , Sweden.
authors.forename: Soniya
authors.initials: S
authors.lastname: Dhanjal
authors.affiliation: a Department of Oncology-Pathology , Cancer Centrum Karolinska (CCK), Karolinska Institutet , Stockholm , Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Henriksson
authors.affiliation: a Department of Oncology-Pathology , Cancer Centrum Karolinska (CCK), Karolinska Institutet , Stockholm , Sweden.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Böhm
authors.affiliation: a Department of Oncology-Pathology , Cancer Centrum Karolinska (CCK), Karolinska Institutet , Stockholm , Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Farnebo
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D020541:Coiled Bodies / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D018832:Molecular Chaperones; D010766:Phosphorylation; D011485:Protein Binding; D011839:Radiation, Ionizing; D019098:Telomerase / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D018832:Molecular Chaperones; D064007:Ataxia Telangiectasia Mutated Proteins; D019098:Telomerase; C535133:WRAP53 protein, human
keywords: ATM; DNA damage response; MDC1; RNF8; TCAB1; WDR79; WRAP53; WRAP53β; phosphorylation; γH2AX