Telomeric states in cancer development

Telomere dysfunction can unleash genome instability or permanently arrest cell proliferation, and thereby contribute to the processes of cancer and aging. Proper telomere function relies on many proteins that form part of its structure. Some telomeric proteins mediate telomere replication whereas others suppress the DNA damage response and DNA repair activities avoiding chromosome end-to-end fusions. However, our knowledge of the telomeric proteome and its pathological perturbations remains incomplete. Progress in telomere research has been partially hampered by a lack of systematic approaches and sensitive tools to analyze telomere composition and function. This thesis provides methodological improvements and applications that have helped to expand the repertoire of proteins involved in protection of telomere integrity. Firstly, this work offers a detailed implementation guide for the Quantitative Telomeric Chromatin Isolation Protocol (QTIP), a mass-spectrometry based technique, which enables identification of telomeric proteins and their quantitative changes between different cell states. Secondly, QTIP is used to characterize the alterations that occur in the telomeric proteome during cellular transformation. I have discovered that proteins involved in telomere DNA replication and DNA damage repair, as well as the telo-meric RNA TERRA are upregulated during cellular transformation. Thirdly, I demonstrate that several of the upregulated proteins counteract telomere fragility, which can be induced by oncogenic stress. SAMHD1 is one of the proteins induced upon cellular transformation. It is frequently mutated in cancer and Aicardi-Goutières syndrome. SAMHD1 association with telomeres is con-firmed and its function explored. I show that SAMHD1 deficiency leads to telomere breakage events when telomere replication is compromised by TRF1 depletion. These results suggest that telomeres break during replication when deprived of TRF1 and that SAMHD1 is required for telomeric DNA damage repair. Finally, the molecular basis of the telomere syndrome caused by CTC1 mutations is examined. Overall, SAMHD1 and CTC1 functions are characterized and added to the conundrum of proteins that facilitate faithful telomere replication.


Advisor(s):
Lingner, Joachim
Year:
2018
Publisher:
Lausanne, EPFL
Keywords:
Laboratories:
UPLIN


Note: The status of this file is: EPFL only


 Record created 2018-03-07, last modified 2019-05-09

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