{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Wen KK"],"funding":["National Institute of Allergy and Infectious Diseases","NIAID NIH HHS","NCI NIH HHS","National Institutes of Health"],"pagination":["324-334"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6949418"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["145(1)"],"pubmed_abstract":["<h4>Background</h4>Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency disorder resulting from Wiskott-Aldrich syndrome protein (WASp) deficiency. Lymphocytes from patients with WAS manifest increased DNA damage and lymphopenia from cell death, yet how WASp influences DNA damage-linked cell survival is unknown. A recently described mechanism promoting cell survival after ionizing radiation (IR)-induced DNA damage involves fragmentation and dispersal of the Golgi apparatus, known as the Golgi-dispersal response (GDR), which uses the Golgi phosphoprotein 3 (GOLPH3)-DNA-dependent protein kinase (DNA-PK)-myosin XVIIIA-F-actin signaling pathway.<h4>Objective</h4>We sought to define WASp's role in the DNA damage-induced GDR and its disruption as a contributor to the development of radiosensitivity-linked immunodeficiency in patients with WAS.<h4>Methods</h4>In human T<sub>H</sub> and B-cell culture systems, DNA damage-induced GDR elicited by IR or radiomimetic chemotherapy was monitored in the presence or absence of WASp or GOLPH3 alone or both together.<h4>Results</h4>WASp deficiency completely prevents the development of IR-induced GDR in human T<sub>H</sub> and B cells, despite the high DNA damage load. Loss of WASp impedes nuclear translocation of GOLPH3 and its colocalization with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Surprisingly, however, depletion of GOLPH3 alone or depolymerization of F-actin in WASp-sufficient T<sub>H</sub> cells still allows development of robust GDR, suggesting that WASp, but not GOLPH3, is essential for GDR and cell survival after IR-induced DNA-damage in human lymphocytes.<h4>Conclusion</h4>The study identifies WASp as a novel effector of the nucleus-to-Golgi cell-survival pathway triggered by IR-induced DNA damage in cells of the hematolymphoid lineage and proposes an impaired GDR as a new cause for development of a \"radiosensitive\" form of immune dysregulation in patients with WAS."],"journal":["The Journal of allergy and clinical immunology"],"pubmed_title":["Wiskott-Aldrich syndrome protein senses irradiation-induced DNA damage to coordinate the cell-protective Golgi dispersal response in human T and B lymphocytes."],"pmcid":["PMC6949418"],"funding_grant_id":["R21AI138051","R21 AI138051","P30 CA086862","R01 AI146380"],"pubmed_authors":["Vyas YM","Wen KK","Han SS"],"additional_accession":[]},"is_claimable":false,"name":"Wiskott-Aldrich syndrome protein senses irradiation-induced DNA damage to coordinate the cell-protective Golgi dispersal response in human T and B lymphocytes.","description":"<h4>Background</h4>Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency disorder resulting from Wiskott-Aldrich syndrome protein (WASp) deficiency. Lymphocytes from patients with WAS manifest increased DNA damage and lymphopenia from cell death, yet how WASp influences DNA damage-linked cell survival is unknown. A recently described mechanism promoting cell survival after ionizing radiation (IR)-induced DNA damage involves fragmentation and dispersal of the Golgi apparatus, known as the Golgi-dispersal response (GDR), which uses the Golgi phosphoprotein 3 (GOLPH3)-DNA-dependent protein kinase (DNA-PK)-myosin XVIIIA-F-actin signaling pathway.<h4>Objective</h4>We sought to define WASp's role in the DNA damage-induced GDR and its disruption as a contributor to the development of radiosensitivity-linked immunodeficiency in patients with WAS.<h4>Methods</h4>In human T<sub>H</sub> and B-cell culture systems, DNA damage-induced GDR elicited by IR or radiomimetic chemotherapy was monitored in the presence or absence of WASp or GOLPH3 alone or both together.<h4>Results</h4>WASp deficiency completely prevents the development of IR-induced GDR in human T<sub>H</sub> and B cells, despite the high DNA damage load. Loss of WASp impedes nuclear translocation of GOLPH3 and its colocalization with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Surprisingly, however, depletion of GOLPH3 alone or depolymerization of F-actin in WASp-sufficient T<sub>H</sub> cells still allows development of robust GDR, suggesting that WASp, but not GOLPH3, is essential for GDR and cell survival after IR-induced DNA-damage in human lymphocytes.<h4>Conclusion</h4>The study identifies WASp as a novel effector of the nucleus-to-Golgi cell-survival pathway triggered by IR-induced DNA damage in cells of the hematolymphoid lineage and proposes an impaired GDR as a new cause for development of a \"radiosensitive\" form of immune dysregulation in patients with WAS.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jan","modification":"2026-05-04T04:25:15.478Z","creation":"2021-02-20T17:40:05Z"},"accession":"S-EPMC6949418","cross_references":{"pubmed":["31604087"],"doi":["10.1016/j.jaci.2019.09.026"]}}