Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies

• DOI: 10.1016/j.molcel.2020.12.030
• Publication Date: 2021-01-18T06:56:17Z
• Authors: Jia-Min Zhang; Marie-Michelle Ge...; Jian Ouyang; Li Lan; Lee Zou
• Keywords: Feedback, Physiological; 0303 health sciences; RecQ Helicases; Intranuclear Inclusion Bodies; Sumoylation; Epithelial Cells; Fibroblasts; Telomere; Protein Inhibitors of Activated STAT; Fanconi Anemia Complementation Group Proteins; Cell Line; Rad52 DNA Repair and Recombination Protein; 03 medical and health sciences; Gene Expression Regulation; Cell Line, Tumor; Gene Knockdown Techniques; Humans; RNA, Small Interfering; Poly-ADP-Ribose Binding Proteins; RNA Helicases; DNA Polymerase III; Signal Transduction

Alternative lengthening of telomeres (ALT) is mediated by break-induced replication (BIR), but how BIR is regulated at telomeres is poorly understood. Here, we show that telomeric BIR is a self-perpetuating process. By tethering PML-IV to telomeres, we induced telomere clustering in ALT-associated PML bodies (APBs) and a POLD3-dependent ATR response at telomeres, showing that BIR generates replication stress. Ablation of BLM helicase activity in APBs abolishes telomere synthesis but causes multiple chromosome bridges between telomeres, revealing a function of BLM in processing inter-telomere BIR intermediates. Interestingly, the accumulation of BLM in APBs requires its own helicase activity and POLD3, suggesting that BIR triggers a feedforward loop to further recruit BLM. Enhancing BIR induces PIAS4-mediated TRF2 SUMOylation, and PIAS4 loss deprives APBs of repair proteins and compromises ALT telomere synthesis. Thus, a BLM-driven and PIAS4-mediated feedforward loop operates in APBs to perpetuate BIR, providing a critical mechanism to extend ALT telomeres.