title: Oral-facial-digital syndrome type I cells exhibit impaired DNA repair; unanticipated consequences of defective OFD1 outside of the cilia network.
abstract: Defects in OFD1 underlie the clinically complex ciliopathy, Oral-Facial-Digital syndrome Type I (OFD Type I). Our understanding of the molecular, cellular and clinical consequences of impaired OFD1 originates from its characterised roles at the centrosome/basal body/cilia network. Nonetheless, the first described OFD1 interactors were components of the TIP60 histone acetyltransferase complex. We find that OFD1 can also localise to chromatin and its reduced expression is associated with mis-localization of TIP60 in patient-derived cell lines. TIP60 plays important roles in controlling DNA repair. OFD Type I cells exhibit reduced histone acetylation and altered chromatin dynamics in response to DNA double strand breaks (DSBs). Furthermore, reduced OFD1 impaired DSB repair via homologous recombination repair (HRR). OFD1 loss also adversely impacted upon the DSB-induced G2-M checkpoint, inducing a hypersensitive and prolonged arrest. Our findings show that OFD Type I patient cells have pronounced defects in the DSB-induced histone modification, chromatin remodelling and DSB-repair via HRR; effectively phenocopying loss of TIP60. These data extend our knowledge of the molecular and cellular consequences of impaired OFD1, demonstrating that loss of OFD1 can negatively impact upon important nuclear events; chromatin plasticity and DNA repair.
authors: Human DNA damage Response Disorders Group, Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Iga
authors: I
authors: Abramowicz
authors: Human DNA damage Response Disorders Group, Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Gillian
authors: G
authors: Carpenter
authors: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors: Mariaevelina
authors: M
authors: Alfieri
authors: Human DNA damage Response Disorders Group, Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Rita
authors: R
authors: Colnaghi
authors: Human DNA damage Response Disorders Group, Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Emily
authors: E
authors: Outwin
authors: Service de Génétique, Centre Hospitalier Universitaire de Brest, France.
authors: Philippe
authors: P
authors: Parent
authors: Centre de Génétique, Hôpital d'Enfants, 14 rue Paul Gaffarel, Dijon Cedex, France.
authors: Christel
authors: C
authors: Thauvin-Robinet
authors: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors: Daniela
authors: D
authors: Iaconis
authors: Telethon Institute of Genetics and Medicine, Naples, Italy.|Department of Medical Translational Sciences, Federico II University, Naples, Italy.
authors: Brunella
authors: B
authors: Franco
authors: Human DNA damage Response Disorders Group, Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
authors: Mark
authors: M
authors: O'Driscoll
mesh_terms: D000107:Acetylation; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002923:Cilia / Q000201:enzymology / Q000473:pathology*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D005347:Fibroblasts; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009958:Orofaciodigital Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*
chemical_list: D002843:Chromatin; D006657:Histones; C115130:OFD1 protein, human; D011506:Proteins; D034741:RNA, Small Interfering