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DONSON encodes a novel replication fork protection factor mutated in 2 microcephalic dwarfism.

ABSTRACT: To ensure efficient genome duplication, cells have evolved a multitude of 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 individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal 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

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Disease Free

SUBMITTER: Alex von kriegsheim

LAB HEAD: alex von kriegsheim

PROVIDER: PXD005690 | Pride | 2017-02-10

REPOSITORIES: Pride

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			Action	DRS
	F151209_02_QE2_jbwills_P_PF_40_1Donson-RB1.raw	Raw
	F151209_03_QE2_jbwills_P_PF_40_1Donson-RB1.raw	Raw
	F151209_04_QE2_jbwills_P_PF_40_2Donson-RB2.raw	Raw
	F151209_05_QE2_jbwills_P_PF_40_2Donson-RB2.raw	Raw
	F151209_06_QE2_jbwills_P_PF_40_3Donson-RB3.raw	Raw

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DONSON encodes a novel replication fork protection factor mutated in 2 microcephalic dwarfism.

Project description:To ensure efficient genome duplication, cells have evolved a multitude of 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 individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal 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

2017-03-28 | MSV000080704 | MassIVE

DONSON encodes a novel replication fork protection factor mutated in microcephalic dwarfism.

Project description:To ensure efficient genome duplication, cells have evolved a multitude of 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 component of the replisome that stabilises forks during normal 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.

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