HMG 2016. ATR Cilia..pdf (981.35 kB)
ATR promotes cilia signalling: links to developmental impacts
journal contribution
posted on 2023-06-09, 00:31 authored by Thomas StiffThomas Stiff, Teresa Casar Tena, Mark O'DriscollMark O'Driscoll, Penny Jeggo, Melanie PhilippMutations 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.
History
Publication status
- Published
File Version
- Published version
Journal
Human Molecular GeneticsISSN
0964-6906Publisher
Oxford University PressExternal DOI
Issue
8Volume
25Page range
1574-1587Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-03-17First Open Access (FOA) Date
2016-03-17First Compliant Deposit (FCD) Date
2016-03-17Usage metrics
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