Reynolds, John J., Bicknell, Louise S., Carroll, Paula, Higgs, Martin R., Shaheen, Ranad, Murray, Jennie E., Papadopoulos, Dimitrios K., Leitch, Andrea, Murina, Olga ORCID: 0000-0003-1650-2892, Tarnauskaite, Zygimante, Wessel, Sarah R., Zlatanou, Anastasia, Vernet, Audrey, von Kriegsheim, Alex ORCID: 0000-0002-4952-8573, Mottram, Rachel M. A., Logan, Clare V., Bye, Hannah, Li, Yun, Brean, Alexander, Maddirevula, Sateesh, Challis, Rachel C., Skouloudaki, Kassiani, Almoisheer, Agaadir, Alsaif, Hessa S., Amar, Ariella, Prescott, Natalie J., Bober, Michael B., Duker, Angela, Faqeih, Eissa, Seidahmed, Mohammed Zain, Al Tala, Saeed, Alswaid, Abdulrahman, Ahmed, Saleem, Al-Aama, Jumana Yousuf, Altmueller, Janine, Al Balwi, Mohammed ORCID: 0000-0003-2910-0390, Brady, Angela F., Chessa, Luciana, Cox, Helen, Fischetto, Rita, Heller, Raoul, Henderson, Bertram D., Hobson, Emma, Nurnberg, Peter, Percin, E. Ferda, Peron, Angela ORCID: 0000-0002-1769-6548, Spaccini, Luigina, Quigley, Alan J., Thakur, Seema, Wise, Carol A., Yoon, Grace, Alnemer, Maha, Tomancak, Pavel ORCID: 0000-0002-2222-9370, Yigit, Goekhan, Taylor, A. Malcolm R., Reijns, Martin A. M., Simpson, Michael A., Cortez, David, Alkuraya, Fowzan S., Mathew, Christopher G., Jackson, Andrew P. and Stewart, Grant S. (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature Genet., 49 (4). S. 537 - 553. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Reynolds, John J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bicknell, Louise S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carroll, PaulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Higgs, Martin R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shaheen, RanadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murray, Jennie E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papadopoulos, Dimitrios K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leitch, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murina, OlgaUNSPECIFIEDorcid.org/0000-0003-1650-2892UNSPECIFIED
Tarnauskaite, ZygimanteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wessel, Sarah R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zlatanou, AnastasiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vernet, AudreyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Kriegsheim, AlexUNSPECIFIEDorcid.org/0000-0002-4952-8573UNSPECIFIED
Mottram, Rachel M. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Logan, Clare V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bye, HannahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brean, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maddirevula, SateeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Challis, Rachel C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Skouloudaki, KassianiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Almoisheer, AgaadirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alsaif, Hessa S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amar, AriellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prescott, Natalie J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bober, Michael B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duker, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faqeih, EissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidahmed, Mohammed ZainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al Tala, SaeedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alswaid, AbdulrahmanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahmed, SaleemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Aama, Jumana YousufUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al Balwi, MohammedUNSPECIFIEDorcid.org/0000-0003-2910-0390UNSPECIFIED
Brady, Angela F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chessa, LucianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cox, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischetto, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heller, RaoulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henderson, Bertram D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hobson, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nurnberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Percin, E. FerdaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peron, AngelaUNSPECIFIEDorcid.org/0000-0002-1769-6548UNSPECIFIED
Spaccini, LuiginaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quigley, Alan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thakur, SeemaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wise, Carol A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yoon, GraceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alnemer, MahaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomancak, PavelUNSPECIFIEDorcid.org/0000-0002-2222-9370UNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylor, A. Malcolm R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reijns, Martin A. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simpson, Michael A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cortez, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alkuraya, Fowzan S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mathew, Christopher G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jackson, Andrew P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stewart, Grant S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-236061
DOI: 10.1038/ng.3790
Journal or Publication Title: Nature Genet.
Volume: 49
Number: 4
Page Range: S. 537 - 553
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MEIER-GORLIN SYNDROME; ORIGIN RECOGNITION COMPLEX; MAINTAIN GENOME INTEGRITY; PRIMORDIAL DWARFISM; GROWTH FAILURE; DNA-DAMAGE; CORRELATION SPECTROSCOPY; CHECKPOINT ACTIVATION; SECKEL-SYNDROME; CELL-CYCLEMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23606

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