Transcriptional Regulation of Telomerase

Summer 2016

Manraj Gill : Molecular and Cell Biology

Mentor: Dr. Dirk Hockemeyer

Human chromosomes end in a repetitive sequence called the telomere. The inability of the DNA replication machinery to fully replicate chromosomes results in progressive telomere shortening with each cell division. Critically short telomeres serve as a signal to stop cellular replication. In this manner, telomeres act as a buffer sequence to prevent loss of genetic information on the chromosomes; a process that is associated with cellular and organismal aging. However, telomerase, a reverse transcriptase, can restore lost telomeric sequence and increase the length of the telomere. In humans, adult stem cells and embryonic stem cells (hESCs) express telomerase but upon differentiation of these stem cells into somatic cells, telomerase expression is silenced. This leads to the progressive telomere shortening in the differentiated cells. Silencing of the telomerase enzyme is a result of transcriptional repression of TERT, the catalytic protein component of telomerase. Interestingly, in 90% of human tumors, TERT transcription is reactivated which allows for continuous tumor growth and the immortal phenotype of cancer cells.

However, the mechanism for TERT silencing and reactivation is not fully understood. I am interested in studying this reactivation of TERT expression during tumor initiation by investigating the promoter region of the TERT gene, the region responsible for regulating transcription. By using CRISPR/Cas9 mediated genome editing in hESCs to uncover which regulatory elements are involved and where specifically they operate, we aim to develop a mechanistic understanding of how this tumor specific switch is mediated.

Many thanks to the Pergo Foundation and the UC Berkeley Summer Undergraduate Research Fellowship program for the support and the opportunity to dedicate time to full-time research during the summer and to my mentors, Kunitoshi Chiba and Dr. Dirk Hockemeyer, for their continual guidance! I really appreciate this assistance because such an opportunity allows for not only a more comprehensive understanding of the research project but also for attaining a better sense of what pursuing graduate studies in the field will be like.