Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

John J. Reynolds; Louise S. Bicknell; Paula Carroll; Martin R. Higgs; Ranad Shaheen; Jennie E. Murray; Dimitrios K. Papadopoulos; Andrea Leitch; Olga Murina; Žygimantė Tarnauskaitė; Sarah R. Wessel; Anastasia Zlatanou; Audrey Vernet; Alex von Kriegsheim; Rachel M A Mottram; Clare V. Logan; Hannah Bye; Yun Li; Alexander Brean; Sateesh Maddirevula; Rachel C. Challis; Kassiani Skouloudaki; Agaadir Almoisheer; Hessa S. Alsaif; Ariella Amar; Natalie J. Prescott; Michael B. Bober; Angela Duker; Eissa Faqeih; Mohammed Zain Seidahmed; Saeed Al Tala; Abdulrahman Alswaid; Saleem Ahmed; Jumana Yousuf Al-Aama; Janine Altmüller; Mohammed Al Balwi; Angela F. Brady; Luciana Chessa; Helen Cox; Rita Fischetto; Raoul Heller; Bertram D. Henderson; Emma Hobson; Peter Nürnberg; E. Ferda Percin; Angela Peron; Luigina Spaccini; Alan J. Quigley; Seema Thakur; Carol A. Wise; Grace Yoon; Maha Alnemer; Pavel Tomancak; Gökhan Yigit; A. Malcolm R Taylor; Martin A M Reijns; Michael A. Simpson; David Cortez; Fowzan S. Alkuraya; Christopher G. Mathew; Andrew P. Jackson; Grant S. Stewart

doi:10.1038/ng.3790

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

John J. Reynolds, Louise S. Bicknell, Paula Carroll, Martin R. Higgs, Ranad Shaheen, Jennie E. Murray, Dimitrios K. Papadopoulos, Andrea Leitch, Olga Murina, Žygimantė Tarnauskaitė, Sarah R. Wessel, Anastasia Zlatanou, Audrey Vernet, Alex von Kriegsheim, Rachel M A Mottram, Clare V. Logan, Hannah Bye, Yun Li, Alexander Brean, Sateesh MaddirevulaRachel C. Challis, Kassiani Skouloudaki, Agaadir Almoisheer, Hessa S. Alsaif, Ariella Amar, Natalie J. Prescott, Michael B. Bober, Angela Duker, Eissa Faqeih, Mohammed Zain Seidahmed, Saeed Al Tala, Abdulrahman Alswaid, Saleem Ahmed, Jumana Yousuf Al-Aama, Janine Altmüller, Mohammed Al Balwi, Angela F. Brady, Luciana Chessa, Helen Cox, Rita Fischetto, Raoul Heller, Bertram D. Henderson, Emma Hobson, Peter Nürnberg, E. Ferda Percin, Angela Peron, Luigina Spaccini, Alan J. Quigley, Seema Thakur, Carol A. Wise, Grace Yoon, Maha Alnemer, Pavel Tomancak, Gökhan Yigit, A. Malcolm R Taylor, Martin A M Reijns, Michael A. Simpson, David Cortez, Fowzan S. Alkuraya, Christopher G. Mathew, Andrew P. Jackson, Grant S. Stewart

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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 downstream neighbor of SON (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 stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

Original language	English (US)
Pages (from-to)	537-549
Number of pages	13
Journal	Nature genetics
Volume	49
Issue number	4
DOIs	https://doi.org/10.1038/ng.3790
State	Published - Mar 30 2017

ASJC Scopus subject areas

Genetics

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Reynolds, J. J., Bicknell, L. S., Carroll, P., Higgs, M. R., Shaheen, R., Murray, J. E., Papadopoulos, D. K., Leitch, A., Murina, O., Tarnauskaitė, Ž., Wessel, S. R., Zlatanou, A., Vernet, A., von Kriegsheim, A., Mottram, R. M. A., Logan, C. V., Bye, H., Li, Y., Brean, A., ... Stewart, G. S. (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature genetics, 49(4), 537-549. https://doi.org/10.1038/ng.3790

Reynolds, JJ, Bicknell, LS, Carroll, P, Higgs, MR, Shaheen, R, Murray, JE, Papadopoulos, DK, Leitch, A, Murina, O, Tarnauskaitė, Ž, Wessel, SR, Zlatanou, A, Vernet, A, von Kriegsheim, A, Mottram, RMA, Logan, CV, Bye, H, Li, Y, Brean, A, Maddirevula, S, Challis, RC, Skouloudaki, K, Almoisheer, A, Alsaif, HS, Amar, A, Prescott, NJ, Bober, MB, Duker, A, Faqeih, E, Seidahmed, MZ, Al Tala, S, Alswaid, A, Ahmed, S, Al-Aama, JY, Altmüller, J, Al Balwi, M, Brady, AF, Chessa, L, Cox, H, Fischetto, R, Heller, R, Henderson, BD, Hobson, E, Nürnberg, P, Percin, EF, Peron, A, Spaccini, L, Quigley, AJ, Thakur, S, Wise, CA, Yoon, G, Alnemer, M, Tomancak, P, Yigit, G, Taylor, AMR, Reijns, MAM, Simpson, MA, Cortez, D, Alkuraya, FS, Mathew, CG, Jackson, AP & Stewart, GS 2017, 'Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism', Nature genetics, vol. 49, no. 4, pp. 537-549. https://doi.org/10.1038/ng.3790

@article{13c76907aeb14c269fe485fa14da1d29,

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 downstream neighbor of SON (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 stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.",

author = "Reynolds, {John J.} and Bicknell, {Louise S.} and Paula Carroll and Higgs, {Martin R.} and Ranad Shaheen and Murray, {Jennie E.} and Papadopoulos, {Dimitrios K.} and Andrea Leitch and Olga Murina and {\v Z}ygimantė Tarnauskaitė and Wessel, {Sarah R.} and Anastasia Zlatanou and Audrey Vernet and {von Kriegsheim}, Alex and Mottram, {Rachel M A} and Logan, {Clare V.} and Hannah Bye and Yun Li and Alexander Brean and Sateesh Maddirevula and Challis, {Rachel C.} and Kassiani Skouloudaki and Agaadir Almoisheer and Alsaif, {Hessa S.} and Ariella Amar and Prescott, {Natalie J.} and Bober, {Michael B.} and Angela Duker and Eissa Faqeih and Seidahmed, {Mohammed Zain} and {Al Tala}, Saeed and Abdulrahman Alswaid and Saleem Ahmed and Al-Aama, {Jumana Yousuf} and Janine Altm{\"u}ller and {Al Balwi}, Mohammed and Brady, {Angela F.} and Luciana Chessa and Helen Cox and Rita Fischetto and Raoul Heller and Henderson, {Bertram D.} and Emma Hobson and Peter N{\"u}rnberg and Percin, {E. Ferda} and Angela Peron and Luigina Spaccini and Quigley, {Alan J.} and Seema Thakur and Wise, {Carol A.} and Grace Yoon and Maha Alnemer and Pavel Tomancak and G{\"o}khan Yigit and Taylor, {A. Malcolm R} and Reijns, {Martin A M} and Simpson, {Michael A.} and David Cortez and Alkuraya, {Fowzan S.} and Mathew, {Christopher G.} and Jackson, {Andrew P.} and Stewart, {Grant S.}",

note = "Funding Information: This work is supported by funding from Cancer Research UK (C17183/A13030) (G.S.S., M.R.H. and A.V.), the Medical Research Council (MR/M009882/1) (J.J.R.), Worldwide Cancer Research (13-1012) (A.Z.), the Birmingham Childrens Hospital Research Foundation (BCHRF400) (R.M.A.M.), the University of Birmingham (J.J.R., R.M.A.M. and A.B.), Newlifethe Charity for Disabled Children (P.C. and L.S.B.), Medical Research Scotland (L.S.B.) and the National Institute for Health Research (NIHR) Biomedical Research Centre at Guys and St. Thomas NHS Foundation Trust and Kings College London (H.B., A. Amar, N.J.P., M.A.S. and C.G.M.), the German Federal Ministry of Education and Research (BMBF) (1GM1404; E-RARE network EuroMicro) (G. Yigit), KSCDR funding and KACST grant 09-MED941-20 (F.S.A.), an EMBO Long-Term Fellowship (ALTF 7-2015) the European Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013-609409) and the Swiss National Science Foundation (P2ZHP3-158709) (O.M.).",

year = "2017",

month = mar,

day = "30",

doi = "10.1038/ng.3790",

language = "English (US)",

volume = "49",

pages = "537--549",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

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

AU - Reynolds, John J.

AU - Bicknell, Louise S.

AU - Carroll, Paula

AU - Higgs, Martin R.

AU - Shaheen, Ranad

AU - Murray, Jennie E.

AU - Papadopoulos, Dimitrios K.

AU - Leitch, Andrea

AU - Murina, Olga

AU - Tarnauskaitė, Žygimantė

AU - Wessel, Sarah R.

AU - Zlatanou, Anastasia

AU - Vernet, Audrey

AU - von Kriegsheim, Alex

AU - Mottram, Rachel M A

AU - Logan, Clare V.

AU - Bye, Hannah

AU - Li, Yun

AU - Brean, Alexander

AU - Maddirevula, Sateesh

AU - Challis, Rachel C.

AU - Skouloudaki, Kassiani

AU - Almoisheer, Agaadir

AU - Alsaif, Hessa S.

AU - Amar, Ariella

AU - Prescott, Natalie J.

AU - Bober, Michael B.

AU - Duker, Angela

AU - Faqeih, Eissa

AU - Seidahmed, Mohammed Zain

AU - Al Tala, Saeed

AU - Alswaid, Abdulrahman

AU - Ahmed, Saleem

AU - Al-Aama, Jumana Yousuf

AU - Altmüller, Janine

AU - Al Balwi, Mohammed

AU - Brady, Angela F.

AU - Chessa, Luciana

AU - Cox, Helen

AU - Fischetto, Rita

AU - Heller, Raoul

AU - Henderson, Bertram D.

AU - Hobson, Emma

AU - Nürnberg, Peter

AU - Percin, E. Ferda

AU - Peron, Angela

AU - Spaccini, Luigina

AU - Quigley, Alan J.

AU - Thakur, Seema

AU - Wise, Carol A.

AU - Yoon, Grace

AU - Alnemer, Maha

AU - Tomancak, Pavel

AU - Yigit, Gökhan

AU - Taylor, A. Malcolm R

AU - Reijns, Martin A M

AU - Simpson, Michael A.

AU - Cortez, David

AU - Alkuraya, Fowzan S.

AU - Mathew, Christopher G.

AU - Jackson, Andrew P.

AU - Stewart, Grant S.

N1 - Funding Information: This work is supported by funding from Cancer Research UK (C17183/A13030) (G.S.S., M.R.H. and A.V.), the Medical Research Council (MR/M009882/1) (J.J.R.), Worldwide Cancer Research (13-1012) (A.Z.), the Birmingham Childrens Hospital Research Foundation (BCHRF400) (R.M.A.M.), the University of Birmingham (J.J.R., R.M.A.M. and A.B.), Newlifethe Charity for Disabled Children (P.C. and L.S.B.), Medical Research Scotland (L.S.B.) and the National Institute for Health Research (NIHR) Biomedical Research Centre at Guys and St. Thomas NHS Foundation Trust and Kings College London (H.B., A. Amar, N.J.P., M.A.S. and C.G.M.), the German Federal Ministry of Education and Research (BMBF) (1GM1404; E-RARE network EuroMicro) (G. Yigit), KSCDR funding and KACST grant 09-MED941-20 (F.S.A.), an EMBO Long-Term Fellowship (ALTF 7-2015) the European Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013-609409) and the Swiss National Science Foundation (P2ZHP3-158709) (O.M.).

PY - 2017/3/30

Y1 - 2017/3/30

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 downstream neighbor of SON (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 stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established 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 downstream neighbor of SON (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 stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

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U2 - 10.1038/ng.3790

DO - 10.1038/ng.3790

M3 - Article

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AN - SCOPUS:85012247268

SN - 1061-4036

VL - 49

SP - 537

EP - 549

JO - Nature genetics

JF - Nature genetics

IS - 4

ER -

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

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