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Title: A mechanistic investigation into candidate markers of telomere-induced senescence in normal human epidermal keratinocytes
Author: dos Santos Soares Martins de Castro, Alicia Maria
ISNI:       0000 0004 5355 367X
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2014
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Telomere dysfunction is one mechanism of cellular and tissue ageing. Dysfunctional telomeres in fibroblasts are recognised as DNA double-strand breaks (DSBs) and trigger the DNA damage pathway of senescence. However, telomere uncapping in normal human epidermal keratinocytes, via expression of the dominant negative mutant of the telomere repeat-binding factor 2 (TRF2!B!M), resulted in a senescent-like arrest without a significant DNA damage response (DDR). This suggests that either keratinocytes are unusually sensitive to telomere uncapping and the low DDR is sufficient to induce senescence or that dysfunctional telomeres may also be signalled through an alternative pathway. Subsequent analysis revealed genes HIST2H2BE, ICEBERG, S100A7 and HOPX as potential markers for telomere dysfunction-induced senescence (TDIS) since they were induced by telomere uncapping and seemed to be regulated by telomerase. The aim of this project was to assess the specificity of these candidate markers for TDIS and to select the most promising for use as a biomarker. To this end, keratinocytes were exposed to doses of ionising radiation, capable of generating transient or permanent damage to the DNA, or transduced with retroviral constructs expressing p14ARF, p16INK4a, p53 or TRF2!B!M and the gene expression levels of the candidates assessed after a recovery period or at the early stages of senescence. Whilst S100A7, HOPX or ICEBERG were not induced by a transient or persistent DDR or by p16INK4a, ICEBERG and HOPX were induced by p53 and p14ARF when these were ectopically expressed at higher levels. Thus, S100A7 seems to be the most specific early marker for telomere dysfunction in keratinocytes since it was selectively induced by telomere uncapping via expression of TRF2!B!M and not by DSBs or by over expression of p14ARF, p53 or p16INK4a. S100A7 may have the potential to identify cells with telomere dysfunction in human epithelia and body fluids.
Supervisor: Not available Sponsor: Age UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: cellular and tissue ageing ; Telomere dysfunction ; DNA damage response ; keratinocytes