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ATR promotes cilia signalling: links to developmental impacts

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posted on 2023-06-09, 00:31 authored by Thomas Stiff, Teresa Casar Tena, Mark O'DriscollMark O'Driscoll, Penny Jeggo, Melanie Philipp
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Human Molecular Genetics

ISSN

0964-6906

Publisher

Oxford University Press

Issue

8

Volume

25

Page range

1574-1587

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-03-17

First Open Access (FOA) Date

2016-03-17

First Compliant Deposit (FCD) Date

2016-03-17

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