ATR promotes cilia signalling: links to developmental impacts

Stiff, Tom, Casar Tena, Teresa, O'Driscoll, Mark, Jeggo, Penny A and Philipp, Melanie (2016) ATR promotes cilia signalling: links to developmental impacts. Human molecular genetics, 25 (8). pp. 1574-1587. ISSN 1460-2083

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QM Human anatomy
Q Science > QM Human anatomy > QM0531 Regional anatomy
Q Science > QP Physiology > QP0351 Neurophysiology and neuropsychology > QP0361 Nervous system
Depositing User: Mark O'Driscoll
Date Deposited: 17 Mar 2016 12:21
Last Modified: 14 Aug 2018 11:06

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