Adrenocortical dysplasia protein homolog (TPP1) (TPP1)

Adrenocortical dysplasia protein homolog (TPP1) is a core component of the shelterin complex, a six-protein assembly that caps and protects the ends of linear chromosomes, known as telomeres (UniProt Q96AP0). The TPP1 protein contains a specific surface motif called the "TEL patch" (comprising residues such as Glu168 and Leu170), which is indispensable for the recruitment of telomerase to telomeric DNA (Zhong et al., 2012, Nature). This interaction between the TPP1-TEL patch and the telomerase reverse transcriptase (TERT) subunit is the primary mechanism by which telomerase is localized to its substrate to counteract telomere shortening (Schmidt et al., 2014, Nature Structural & Molecular Biology). In approximately 90% of human cancers, telomerase is upregulated to maintain telomere length and support indefinite cell proliferation, making the TPP1-TEL patch interface a high-priority target for anti-cancer drug development (Grill et al., 2019, Nature Communications). Conversely, germline mutations in the TEL patch lead to telomere biology disorders, including dyskeratosis congenita and idiopathic pulmonary fibrosis, due to insufficient telomere maintenance (PubMed: 22522920). Therapeutic strategies currently focus on small molecule inhibitors that disrupt the TPP1-TERT interaction to induce senescence in malignant cells, though these must be carefully designed to avoid toxicity in telomerase-dependent healthy stem cells.

Other names

ACDPIP1PTOPTINT1Shelterin complex subunit TPP1TPP1-TEL patchAdrenocortical dysplasia protein

Inhibition of telomerase recruitment to telomeres by disrupting the interaction between the TPP1-TEL patch and the TERT TEN domain