Tpp1, also known as ACD (alternate name), is a component of the shelterin complex. It plays a crucial role in maintaining genome stability by protecting telomeric DNA and recruiting telomerase to chromosome ends, counterbalancing telomere shortening during cell division. This process is essential for normal cell proliferation, especially in germ and stem cells, and is also involved in preventing unwanted end-joining of chromosomes [1,3].

In mouse hematopoietic stem cells (mHSCs), mutagenesis of Tpp1 in its TIN2-and POT1-binding domains was carried out. TIN2-and POT1-binding mutants were unable to rescue mHSC failure resulting from end deprotection, while Tpp1 telomeropathy mutations sustained mHSC viability, indicating their selective impact on end replication. This shows how different Tpp1 mutations can have distinct effects on hematopoietic stem cell function, highlighting the importance of Tpp1's interactions in telomere-related processes [2].

In conclusion, Tpp1 is essential for telomere maintenance, which is crucial for genome stability and normal cell proliferation. The study of Tpp1 through mutagenesis in mouse models, such as in mHSCs, has provided insights into its role in telomere-related processes and diseases. These findings contribute to understanding the mechanisms underlying telomere-associated diseases and may potentially lead to new therapeutic strategies [2].

References:

1. Aramburu, Tomas, Plucinsky, Sarah, Skordalakes, Emmanuel. 2020. POT1-TPP1 telomere length regulation and disease. In Computational and structural biotechnology journal, 18, 1939-1946. doi:10.1016/j.csbj.2020.06.040. https://pubmed.ncbi.nlm.nih.gov/32774788/

2. Grill, Sherilyn, Padmanaban, Shilpa, Friedman, Ann, Maillard, Ivan, Nandakumar, Jayakrishnan. 2021. TPP1 mutagenesis screens unravel shelterin interfaces and functions in hematopoiesis. In JCI insight, 6, . doi:10.1172/jci.insight.138059. https://pubmed.ncbi.nlm.nih.gov/33822766/

3. Rajavel, Malligarjunan, Mullins, Michael R, Taylor, Derek J. 2014. Multiple facets of TPP1 in telomere maintenance. In Biochimica et biophysica acta, 1844, 1550-9. doi:10.1016/j.bbapap.2014.04.014. https://pubmed.ncbi.nlm.nih.gov/24780581/