Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

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@article{8ac7e6fe51424899860a568380ab1b4e,
title = "Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism",
abstract = "To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilises forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.",
keywords = "Microcephaly, Microcephalic dwarfism , DNA Damage, ATR, DNA Replication, Replication Stress, DONSON",
author = "John Reynolds and Martin Higgs and Anastasia Zlatanou and Audrey Vernet and Malcolm Taylor and Grant Stewart",
year = "2017",
doi = "10.1038/ng.3790",
language = "English",
volume = "49",
pages = "537–549",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

AU - Reynolds, John

AU - Higgs, Martin

AU - Zlatanou, Anastasia

AU - Vernet, Audrey

AU - Taylor, Malcolm

AU - Stewart, Grant

PY - 2017

Y1 - 2017

N2 - To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilises forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

AB - To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilises forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

KW - Microcephaly

KW - Microcephalic dwarfism

KW - DNA Damage

KW - ATR

KW - DNA Replication

KW - Replication Stress

KW - DONSON

U2 - 10.1038/ng.3790

DO - 10.1038/ng.3790

M3 - Article

VL - 49

SP - 537

EP - 549

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -