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Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of meier-gorlin syndrome

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posted on 2023-06-08, 14:39 authored by Thomas StiffThomas Stiff, Meryem Alagoz, Diana AlcantaraDiana Alcantara, Emily OutwinEmily Outwin, Han G Brunner, Ernie M H F Bongers, Mark O'DriscollMark O'Driscoll, Penny Jeggo
Mutations in ORC1, ORC4, ORC6, CDT1, and CDC6, which encode proteins required for DNA replication origin licensing, cause Meier-Gorlin syndrome (MGS), a disorder conferring microcephaly, primordial dwarfism, underdeveloped ears, and skeletal abnormalities. Mutations in ATR, which also functions during replication, can cause Seckel syndrome, a clinically related disorder. These findings suggest that impaired DNA replication could underlie the developmental defects characteristic of these disorders. Here, we show that although origin licensing capacity is impaired in all patient cells with mutations in origin licensing component proteins, this does not correlate with the rate of progression through S phase. Thus, the replicative capacity in MGS patient cells does not correlate with clinical manifestation. However, ORC1-deficient cells from MGS patients and siRNA-mediated depletion of origin licensing proteins also have impaired centrosome and centriole copy number. As a novel and unexpected finding, we show that they also display a striking defect in the rate of formation of primary cilia. We demonstrate that this impacts sonic hedgehog signalling in ORC1-deficient primary fibroblasts. Additionally, reduced growth factor-dependent signaling via primary cilia affects the kinetics of cell cycle progression following cell cycle exit and re-entry, highlighting an unexpected mechanism whereby origin licensing components can influence cell cycle progression. Finally, using a cell-based model, we show that defects in cilia function impair chondroinduction. Our findings raise the possibility that a reduced efficiency in forming cilia could contribute to the clinical features of MGS, particularly the bone development abnormalities, and could provide a new dimension for considering developmental impacts of licensing deficiency.

History

Publication status

  • Published

File Version

  • Published version

Journal

PLoS Genetics

ISSN

1553-7404

Publisher

Public Library of Science

Issue

3

Volume

9

Article number

e1003360

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2013-04-05

First Open Access (FOA) Date

2014-03-12

First Compliant Deposit (FCD) Date

2014-03-12

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