Ca2+-Stimulated AMPK-Dependent Phosphorylation of Exo1 Protects Stressed Replication Forks from Aberrant Resection

Shan Li, Zeno Lavagnino, Delphine Lemacon, Lingzhen Kong, Alessandro Ustione, Xuewen Ng, Yuanya Zhang, Yingchun Wang, Bin Zheng, Helen Piwnica-Worms, Alessandro Vindigni, David W. Piston, Zhongsheng You

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Abnormal processing of stressed replication forks by nucleases can cause fork collapse, genomic instability, and cell death. Despite its importance, it is poorly understood how the cell properly controls nucleases to prevent detrimental fork processing. Here, we report a signaling pathway that controls the activity of exonuclease Exo1 to prevent aberrant fork resection during replication stress. Our results indicate that replication stress elevates intracellular Ca2+ concentration ([Ca2+]i), leading to activation of CaMKK2 and the downstream kinase 5′ AMP-activated protein kinase (AMPK). Following activation, AMPK directly phosphorylates Exo1 at serine 746 to promote 14-3-3 binding and inhibit Exo1 recruitment to stressed replication forks, thereby avoiding unscheduled fork resection. Disruption of this signaling pathway results in excessive ssDNA, chromosomal instability, and hypersensitivity to replication stress inducers. These findings reveal a link between [Ca2+]i and the replication stress response as well as a function of the Ca2+-CaMKK2-AMPK signaling axis in safeguarding fork structure to maintain genome stability.

Original languageEnglish
Pages (from-to)1123-1137.e6
JournalMolecular cell
Volume74
Issue number6
DOIs
StatePublished - Jun 20 2019

Keywords

  • 14-3-3
  • AMPK
  • Ca
  • CaMKK2
  • Exo1
  • calcium signaling
  • genome maintenance
  • protein phosphorylation
  • replication fork resection
  • replication stress response

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