Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis

• Published in: Cell reports (Cambridge) Vol. 15; no. 10; pp. 2170 - 2184
• Main Authors: Pinzaru, Alexandra M., Hom, Robert A., Beal, Angela, Phillips, Aaron F., Ni, Eric, Cardozo, Timothy, Nair, Nidhi, Choi, Jaehyuk, Wuttke, Deborah S., Sfeir, Agnel, Denchi, Eros Lazzerini
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.06.2016; Elsevier
• Subjects: Amino Acid Sequence; Animals; Ataxia Telangiectasia Mutated Proteins - metabolism; ATR; Carcinogenesis - metabolism; Carcinogenesis - pathology; cutaneous T cell lymphoma; DNA Damage - genetics; DNA Repair - genetics; DNA Replication; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Genetic Predisposition to Disease; Genomic Instability; Lymphoid Progenitor Cells - metabolism; Lymphoma, T-Cell, Cutaneous - genetics; Lymphoma, T-Cell, Cutaneous - immunology; Lymphoma, T-Cell, Cutaneous - pathology; Mice; Mutant Proteins - metabolism; Mutation - genetics; POT1; Protein Binding; replication stress; Stress, Physiological; telomere; Telomere - metabolism; thymic lymphoma; Thymus Gland - pathology; Tumor Suppressor Protein p53 - metabolism; POT1; replication stress; thymic lymphoma; telomere; cutaneous T cell lymphoma; ATR
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.05.008

Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis. [Display omitted] •CTCL-associated POT1 mutations lead to telomere replication defects•POT1 mutations compromise the function of the CST complex at telomeres•Inactivation of POT1a promotes genomic instability and enhances tumorigenesis•Attenuation of ATR signaling in POT1a/p53 double knockout tumors Pinzaru et al. define a role for POT1 inactivation in the onset of thymic lymphomas. Inhibition of POT1 causes replication defects at telomeres resulting in telomere fragility, replication fork stalling, and genome instability. These results suggest a role for defective telomere replication during tumorigenesis.