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ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability.
Chen, Siyuan; Pan, Chen; Huang, Jun; Liu, Ting.
Afiliación
  • Chen S; Zhejiang Provincial Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
  • Pan C; The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 310058, Hangzhou, China.
  • Huang J; The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 310058, Hangzhou, China.
  • Liu T; Zhejiang Provincial Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China. jhuang@zju.edu.cn.
EMBO J ; 43(7): 1301-1324, 2024 Apr.
Article en En | MEDLINE | ID: mdl-38467834
ABSTRACT
Upon replication fork stalling, the RPA-coated single-stranded DNA (ssDNA) formed behind the fork activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase, concomitantly initiating Rad18-dependent monoubiquitination of PCNA. However, whether crosstalk exists between these two events and the underlying physiological implications of this interplay remain elusive. In this study, we demonstrate that during replication stress, ATR phosphorylates human Rad18 at Ser403, an adjacent residue to a previously unidentified PIP motif (PCNA-interacting peptide) within Rad18. This phosphorylation event disrupts the interaction between Rad18 and PCNA, thereby restricting the extent of Rad18-mediated PCNA monoubiquitination. Consequently, excessive accumulation of the tumor suppressor protein SLX4, now characterized as a novel reader of ubiquitinated PCNA, at stalled forks is prevented, contributing to the prevention of stalled fork collapse. We further establish that ATR preserves telomere stability in alternative lengthening of telomere (ALT) cells by restricting Rad18-mediated PCNA monoubiquitination and excessive SLX4 accumulation at telomeres. These findings shed light on the complex interplay between ATR activation, Rad18-dependent PCNA monoubiquitination, and SLX4-associated stalled fork processing, emphasizing the critical role of ATR in preserving replication fork stability and facilitating telomerase-independent telomere maintenance.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Telomerasa Límite: Humans Idioma: En Revista: EMBO J Año: 2024 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Telomerasa Límite: Humans Idioma: En Revista: EMBO J Año: 2024 Tipo del documento: Article País de afiliación: China