Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.
Mol Cell
; 81(5): 1027-1042.e4, 2021 03 04.
Article
em En
| MEDLINE
| ID: mdl-33453166
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Telômero
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RNA Helicases
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Retroalimentação Fisiológica
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Proteína 2 de Ligação a Repetições Teloméricas
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Proteínas Inibidoras de STAT Ativados
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Proteínas de Grupos de Complementação da Anemia de Fanconi
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Homeostase do Telômero
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Proteínas de Ligação a Poli-ADP-Ribose
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article