期刊
EMBO REPORTS
卷 19, 期 9, 页码 -出版社
WILEY
DOI: 10.15252/embr.201846263
关键词
fork stabilization; synthetic lethality; PARP inhibitors
资金
- Ministry of Science and Technology of the People's Republic of China [2016YFA0100301]
- National Program on Key Basic Research Project (973 Program) [2015CB553405]
- Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents [2016-63]
- National Natural Science Foundation of China
- Zhejiang Provincial Natural Science Foundation
- National 1000 Talents Program
- Swedish Research Council
- Swedish Cancer Society
- Swedish Children's Cancer Foundation
- Swedish Pain Relief Foundation
Timely and faithful duplication of the entire genome depends on completion of replication. Replication forks frequently encounter obstacles that may cause genotoxic fork stalling. Nevertheless, failure to complete replication rarely occurs under normal conditions, which is attributed to an intricate network of proteins that serves to stabilize, repair and restart stalled forks. Indeed, many of the components in this network are encoded by tumour suppressor genes, and their loss of function by mutation or deletion generates genomic instability, a hallmark of cancer. Paradoxically, the same fork-protective network also confers resistance of cancer cells to chemotherapeutic drugs that induce high-level replication stress. Here, we review the mechanisms and major pathways rescuing stalled replication forks, with a focus on fork stabilization preventing fork collapse. A coherent understanding of how cells protect their replication forks will not only provide insight into how cells maintain genome stability, but also unravel potential therapeutic targets for cancers refractory to conventional chemotherapies.
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