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DNA repair is limiting for haematopoietic stem cells during ageing

Nijnik, Anastasia; Woodbine, Lisa; Marchetti, Caterina; Dawson, Sarah; Lambe, Teresa; Liu, Cong; Rodrigues, Neil P.; Crockford, Tanya; Cabuy, Erik; Vindigni, Alessandro; Enver, Tariq; Bell, John I; Slijepcevic, Predrag; Goodnow, Christopher; Jeggo, Penelope A.; Cornall, Richard J

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Accumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of ageing. Here we address this question by taking advantage of the highly specific role of DNA ligase IV in the repair of DNA double-strand breaks by non-homologous end-joining, and by the discovery of a unique mouse strain with a hypomorphic Lig4Y288C mutation. The Lig4Y288C mouse, identified by means of a mutagenesis screening programme, is a mouse model for human LIG4 syndrome,...[Show more]

dc.contributor.authorNijnik, Anastasia
dc.contributor.authorWoodbine, Lisa
dc.contributor.authorMarchetti, Caterina
dc.contributor.authorDawson, Sarah
dc.contributor.authorLambe, Teresa
dc.contributor.authorLiu, Cong
dc.contributor.authorRodrigues, Neil P.
dc.contributor.authorCrockford, Tanya
dc.contributor.authorCabuy, Erik
dc.contributor.authorVindigni, Alessandro
dc.contributor.authorEnver, Tariq
dc.contributor.authorBell, John I
dc.contributor.authorSlijepcevic, Predrag
dc.contributor.authorGoodnow, Christopher
dc.contributor.authorJeggo, Penelope A.
dc.contributor.authorCornall, Richard J
dc.date.accessioned2015-12-07T22:52:38Z
dc.identifier.issn0028-0836
dc.identifier.urihttp://hdl.handle.net/1885/27506
dc.description.abstractAccumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of ageing. Here we address this question by taking advantage of the highly specific role of DNA ligase IV in the repair of DNA double-strand breaks by non-homologous end-joining, and by the discovery of a unique mouse strain with a hypomorphic Lig4Y288C mutation. The Lig4Y288C mouse, identified by means of a mutagenesis screening programme, is a mouse model for human LIG4 syndrome, showing immunodeficiency and growth retardation. Diminished DNA double-strand break repair in the Lig4Y288C strain causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during ageing, and severely impairs stem cell function in tissue culture and transplantation. The sensitivity of haematopoietic stem cells to non-homologous end-joining deficiency is therefore a key determinant of their ability to maintain themselves against physiological stress over time and to withstand culture and transplantation.
dc.publisherMacmillan Publishers Ltd
dc.sourceNature
dc.subjectKeywords: dna ligase iv; polydeoxyribonucleotide synthase; unclassified drug; DNA; enzyme activity; genetic analysis; growth response; mutation; physiology; rodent; animal experiment; animal model; article; bone marrow; cell aging; cell function; cell loss; control
dc.titleDNA repair is limiting for haematopoietic stem cells during ageing
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume447
dc.date.issued2007
local.identifier.absfor110704 - Cellular Immunology
local.identifier.ariespublicationu6800332xPUB51
local.type.statusPublished Version
local.contributor.affiliationNijnik, Anastasia, Oxford University
local.contributor.affiliationWoodbine, Lisa, University of Sussex
local.contributor.affiliationMarchetti, Caterina, University of Sussex
local.contributor.affiliationDawson, Sarah, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLambe, Teresa, Oxford University
local.contributor.affiliationLiu, Cong, University of Sussex
local.contributor.affiliationRodrigues, Neil P., Oxford University
local.contributor.affiliationCrockford, Tanya, University of Oxford
local.contributor.affiliationCabuy, Erik, Brunel University
local.contributor.affiliationVindigni, Alessandro, International Centre for Genetic Engineering and Biotechology
local.contributor.affiliationEnver, Tariq, Oxford University
local.contributor.affiliationBell, John I, University of Oxford
local.contributor.affiliationSlijepcevic, Predrag, Brunel University
local.contributor.affiliationGoodnow, Christopher, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationJeggo, Penelope A., University of Sussex
local.contributor.affiliationCornall, Richard J, Oxford University
local.description.embargo2037-12-31
local.bibliographicCitation.startpage686
local.bibliographicCitation.lastpage691
local.identifier.doi10.1038/nature05875
dc.date.updated2015-12-07T12:31:28Z
local.identifier.scopusID2-s2.0-34250001450
CollectionsANU Research Publications

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