title: DNA damage response defect in Williams-Beuren syndrome.
abstract: Williams-Beuren syndrome (WBS, no. OMIM 194050) is a rare multisystem genetic disorder caused by a microdeletion on chromosome 7q11.23 and characterized by cardiovascular malformations, mental retardation, and a specific facial dysmorphism. Recently, we reported that a series of non‑Hodgkin's lymphoma occurs in children with WBS and thus hypothesized that a predisposition to cancer may be associated with this genetic disorder. The aim of the present study was to ascertain the role played by three genes hemizygously deleted in WBS (RFC2, GTF2I and BAZ1B) in DNA damage response pathways. Cell proliferation, cell cycle analysis, γ‑H2A.X induction, and expression of DNA damage response proteins were investigated upon exposure to genotoxic treatments in WBS patient‑derived primary fibroblasts and in the 293T cell line treated with specific siRNAs targeting RFC2, GTF2I and BAZ1B. An impaired hydroxyurea‑induced phosphorylation of CHK1 was observed in the WBS cells. However, this defective DNA damage response was not associated with an increased sensitivity to genotoxic agents. In addition, depletion of RFC2, GTF2I and BAZ1B using specific siRNAs did not have a significant impact on the DNA damage response in 293T cells. Our results highlight that the ATR‑dependent DNA damage response is impaired in WBS patient cells but is also dispensable for viability when these cells undergo a genotoxic stress. The mechanism by which the ATR pathway is impaired in WBS warrants elucidation through further investigation.
authors.affiliation: Laboratory of Cellular and Molecular Biology, University Hospital of Besançon, F-25000 Besançon, France.
authors.forename: David
authors.initials: D
authors.lastname: Guenat
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia I‑71013, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merla
authors.affiliation: Inserm UMR1098/EFS‑BFC/University of Franche‑Comte, LabEx LipSTIC, F-25000 Besançon, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deconinck
authors.affiliation: Inserm UMR1098/EFS‑BFC/University of Franche‑Comte, LabEx LipSTIC, F-25000 Besançon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.affiliation: Inserm UMR1098/EFS‑BFC/University of Franche‑Comte, LabEx LipSTIC, F-25000 Besançon, France.
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Rohrlich
mesh_terms: D016022:Case-Control Studies; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D018980:Williams Syndrome / Q000235:genetics* / Q000378:metabolism
chemical_list: D006657:Histones; D034741:RNA, Small Interfering; D005047:Etoposide; D006918:Hydroxyurea