Chun-on, Pattra
(2023)
Recurrent TPP1 Promoter Mutations Drive Telomere Maintenance in Melanoma.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Limitless replicative potential is a defining hallmark of cancer. Somatic cells are limited in their replicative potential by telomere shortening. Telomeres are caps on the ends of chromosomes that shorten as cells divide. Telomere maintenance in cancer cells typically depends on the reactivation of telomerase, an enzyme that synthesizes new telomeres, to allow somatic cells to bypass replicative senescence.
TERT is the reverse transcriptase component of telomerase. Mutations in the TERT promoter have been found in ~75% of melanomas and create the de novo E-twenty six (ETS) transcription factor binding motifs that function to increase TERT expression. The acquisition of TERT promoter mutations can extend the proliferative capacity of cells but cannot prevent bulk telomere shortening and, therefore, cells remain mortal. Additional somatic alterations are required for cells to become fully immortal.
TPP1 is a component of the shelterin complex that coats telomeres. TPP1 was previously reported to have two isoforms: TPP1-L encompasses 544 amino acids (aa) and TPP1-S, a 458 aa protein that initiates at Met87 of TPP1-L. Here, we identified a cluster of variants at the 5′ region of the ACD gene encoding TPP1 in cutaneous melanoma. These variants are TPP1-S promoter variants but not TPP1-L coding variants. The two most common re-occurring variants, -108 C>T and -75 C>T, in the TPP1 promoter create the de novo ETS binding sites and increase TPP1 expression similar to what is seen with the most common TERT promoter mutations.
We find that TPP1 acts synergistically with TERT to lengthen telomeres in primary BJ fibroblasts. CRISPR/Cas9-mediated genome editing that introduced TPP1 promoter variants into human melanomas led to increased TPP1 activity and significantly increased telomerase activity.
Co-occurrence of TERT promoter mutations and TPP1 promoter variants was identified in ~5% of cutaneous melanomas by whole genome sequencing analysis, suggesting that TPP1 promoter variants cooperate with TERT promoter mutations to enhance telomere maintenance and immortalization in melanoma. The findings of this study could potentially be translated and applied in the clinical care of melanoma and other types of cancers.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
15 May 2023 |
| Date Type: |
Publication |
| Defense Date: |
7 April 2023 |
| Approval Date: |
15 May 2023 |
| Submission Date: |
11 April 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
137 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Environmental and Occupational Health |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
telomere, telomerase, shelterin, TERT, TPP1, ACD, melanoma |
| Date Deposited: |
15 May 2023 22:23 |
| Last Modified: |
15 May 2023 22:23 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44516 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}