Dyskeratosis congenita and the DNA damage response

Kirwan, Michael and Beswick, Richard and Walne, Amanda J. and Hossain, Upal and Casimir, Colin M. and Vulliamy, Tom and Dokal, Inderjeet (2011) Dyskeratosis congenita and the DNA damage response. British Journal of Haematology,, 153 (5). pp. 634-643. ISSN 0007-1048

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Official URL: http://dx.doi.org/10.1111/j.1365-2141.2011.08679.x

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Abstract

Dyskeratosis congenita (DC) is a heterogeneous bone marrow failure disorder with known mutations in components of telomerase and telomere shelterin. Recent work in a mouse model with a dyskerin mutation has implicated an increased DNA damage response as part of the cellular pathology, while mouse models with Terc and Tert mutations displayed a normal response. To clarify how these contradictory results might apply to DC pathology in humans, we studied the cellular phenotype in primary cells from DC patients of several genetic subtypes, focussing on T lymphocytes to remain close to the haematopoietic system. We observed novel cell cycle abnormalities in conjunction with impaired growth and an increase in apoptosis. Using flow cytometry and confocal microscopy we examined induction of the DNA damage proteins -H2AX and 53BP1 and the cell cycle protein TP53 (p53). We found an increase in damage foci at telomeres in lymphocytes and an increase in the basal level of DNA damage in fibroblasts, but crucially no increased response to DNA damaging agents in either cell type. As the response to induced DNA damage was normal and levels of global DNA damage were inconsistent between cell types, DNA damage may contribute differently to the pathology in different tissues.

Item Type:Article
Research Areas:Middlesex University Schools and Centres > School of Science and Technology > Natural Sciences
Middlesex University Schools and Centres > School of Science and Technology > Natural Sciences > Molecular Biology group
Citations on ISI Web of Science:2
ID Code:7924
Deposited On:01 Jun 2011 08:02
Last Modified:09 Oct 2014 11:56

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