title: ATR promotes cilia signalling: links to developmental impacts.
abstract: Mutations in ATR(ataxia telangiectasia and RAD3-related) cause Seckel syndrome (ATR-SS), a microcephalic primordial dwarfism disorder. Hitherto, the clinical manifestation of ATR deficiency has been attributed to its canonical role in DNA damage response signalling following replication fork stalling/collapse. Here, we show that ATR regulates cilia-dependent signalling in a manner that can be uncoupled from its function during replication. ATR-depleted or patient-derived ATR-SS cells form cilia of slightly reduced length but are dramatically impaired in cilia-dependent signalling functions, including growth factor and Sonic hedgehog signalling. To better understand the developmental impact of ATR loss of function, we also used zebrafish as a model. Zebrafish embryos depleted of Atr resembled ATR-SS morphology, showed a modest but statistically significant reduction in cilia length and other morphological features indicative of cilia dysfunction. Additionally, they displayed defects in left-right asymmetry including ambiguous expression of southpaw, incorrectly looped hearts and randomized localization of internal organs including the pancreas, features typically conferred by cilia dysfunction. Our findings reveal a novel role for ATR in cilia signalling distinct from its canonical function during replication and strengthen emerging links between cilia function and development.
authors.affiliation: Double Strand Break Repair Laboratory and.
authors.forename: Tom
authors.initials: T
authors.lastname: Stiff
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, 89081 Ulm, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Casar Tena
authors.affiliation: Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK and m.0-driscoll@sussex.ac.uk p.a.jeggo@sussex.ac.uk melanie.philipp@uni-ulm.de.
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.affiliation: Double Strand Break Repair Laboratory and, m.0-driscoll@sussex.ac.uk p.a.jeggo@sussex.ac.uk melanie.philipp@uni-ulm.de.
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, 89081 Ulm, Germany m.0-driscoll@sussex.ac.uk p.a.jeggo@sussex.ac.uk melanie.philipp@uni-ulm.de.
authors.forename: Melanie
authors.initials: M
authors.lastname: Philipp
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002923:Cilia / Q000378:metabolism / Q000473:pathology*; D004261:DNA Replication; D004195:Disease Models, Animal; D004392:Dwarfism / Q000235:genetics / Q000473:pathology*; D019066:Facies; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008831:Microcephaly / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins; C576597:ATR protein, human; C000612702:ATR protein, zebrafish; D064007:Ataxia Telangiectasia Mutated Proteins