Two Separation-of-Function Isoforms of Human TPP1 Dictate Telomerase Regulation in Somatic and Germ Cells
Year: 2019
Type: article
Abstract: Telomerase replicates chromosome ends in germ and somatic stem cells to facilitate their continued proliferation. Telomerase action depends on the telomeric protein TPP1, which recruits telomerase to telomeres and facilitates processive DNA synthesis. Here, we identify separation-of-function long (TPP1-L) and short (TPP1-S) isoforms of TPP1 that appear to be generated from separate transcripts and differ only in 86 amino acids at their N terminus. Although both isoforms retain the ability to recruit telomerase, only TPP1-S facilitates efficient telomere synthesis. We find that TPP1-S is the predominant isoform in somatic cells, and strikingly, TPP1-L is the major isoform in differentiated male germ cells. We observed that TERT expression persists in these germ cells, suggesting that TPP1-L could restrain telomerase in this context. We show how differential expression of TPP1 isoforms determines telomerase function and demonstrate how alternative transcription start sites allow one gene to perform distinct functions in different biological contexts.
Source: Cell Reports
Institution: University of Michigan
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: American Cancer Society, Center for Outcomes Research and Evaluation, Yale School of Medicine, University of Michigan, National Institutes of Health, Michigan Institute for Data Science, University of Michigan, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Elucidating the Role of TCF21+ Mesenchymal Cells in Testis Tissue Homeostasis and Regeneration, G2252980106, Michigan Medical Scientist Training Program, Michigan Predoctoral Training in Genetics, G3446743214, Telomeric Protein Function and Regulation, Dissecting the roles of TPP1 in telomere lengthening (Second Re-submission), Molecular functions of the shelterin component ACD/TPP1 in somatic stem cells and tissue homeostasis, G7294522885, Contributions of Sperm Chromatin to development: A Myth or Reality?, Comprehensive mapping of mouse testis cell types and spermatogenic stages by single-cell RNA sequencing, Career Training in Reproductive Biology
OpenAlex ID: W2950467078