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

Li, Shan; Lavagnino, Zeno; Lemaçon, Delphine; Kong, Lingzhen; Ustione, Alessandro; Ng, Xuewen; Zhang, Yuanya; Wang, Yingchun; Zheng, Bin; Piwnica‐Worms, Helen; Vindigni, Alessandro; Piston, David W.; You, Zhipeng

doi:10.1016/j.molcel.2019.04.003

Cited by 68 publications

(68 citation statements)

References 90 publications

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“…Human EXO1 is phosphorylated by ATR, which promotes ubiquitylation‐dependent degradation of EXO1 and prevents chromosome fragmentation due to unrestrained EXO1 processing activity (El‐Shemerly et al , ; Tomimatsu et al , ). CHK1 also phosphorylates EXO1 directly on serine 746, creating a docking site for binding to 14‐3‐3 proteins, which prevent recruitment of EXO1 to chromatin and limit EXO1 action at stalled forks (Engels et al , ; Li et al , ). In addition, ATR governs the recruitment and/or stability of several helicases important for remodeling the stalled fork and promoting fork restart.…”

Section: Introductionmentioning

confidence: 99%

DNA damage kinase signaling: checkpoint and repair at 30 years

2019

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From bacteria to mammalian cells, damaged DNA is sensed and targeted by DNA repair pathways. In eukaryotes, kinases play a central role in coordinating the DNA damage response. DNA damage signaling kinases were identified over two decades ago and linked to the cell cycle checkpoint concept proposed by Weinert and Hartwell in 1988. Connections between the DNA damage signaling kinases and DNA repair were scant at first, and the initial perception was that the importance of these kinases for genome integrity was largely an indirect effect of their roles in checkpoints, DNA replication, and transcription. As more substrates of DNA damage signaling kinases were identified, it became clear that they directly regulate a wide range of DNA repair factors. Here, we review our current understanding of DNA damage signaling kinases, delineating the key substrates in budding yeast and humans. We trace the progress of the field in the last 30 years and discuss our current understanding of the major substrate regulatory mechanisms involved in checkpoint responses and DNA repair.

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Section: Introductionmentioning

confidence: 99%

DNA damage kinase signaling: checkpoint and repair at 30 years

2019

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“…The results suggest that despite the absence of significant changes in Nedd4‐2’s association with membranes, Ca 2+ influx promotes C2‐containing Nedd4‐2‐mediated ubiquitination of GluA1. This could potentially be resulted from the crosstalk between Ca 2+ and 14‐3‐3, as the functions of 14‐3‐3 are known to be affected by Ca 2+ (Zhitomirsky et al ; Li et al ). The results, together with our findings in Fig.…”

Section: Resultsmentioning

confidence: 99%

C2‐lacking isoform of Nedd4‐2 regulates excitatory synaptic strength through GluA1 ubiquitination‐independent mechanisms

Zhu

Lee

Jong

et al. 2019

Journal of Neurochemistry

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Neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2) is an epilepsy-associated gene, which encodes a ubiquitin E3 ligase that is highly expressed in the brain. Nedd4-2's substrates include many ion channels and receptors because its N-terminal C2 domain guides Nedd4-2 to the cell membrane. We previously found that Nedd4-2 ubiquitinates the glutamate receptor subunit 1 (GluA1) subunit of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, which leads to reduction of neuronal excitability and seizures in mice. However, despite awareness of a Nedd4-2 isoform with no C2 domain, the functions of this isoform remain elusive. In this study, we showed that the C2-lacking Nedd4-2 has reduced membrane distribution and exhibits reduced affinity toward ubiquitinating GluA1. However, when expressed in primary cortical neurons, we found that the C2-lacking Nedd4-2 exhibits a similar activity toward reducing excitatory synaptic strength as does the C2containing Nedd4-2. In an attempt to identify novel Nedd4-2 substrates that could mediate excitatory synaptic strength, we used unbiased proteomic screening and found multiple synaptic regulators that were up-regulated in the brain of conditional Nedd4-2 knockout mice, including protein phosphatase 3 catalytic subunit-a (PPP3CA; alternately called calcineurin A-a). We confirmed PPP3CA as a substrate of the C2-lacking Nedd4-2 and showed that all three epilepsyassociated missense mutations of Nedd4-2 disrupted PPP3CA ubiquitination. Altogether, our results revealed novel potential Nedd4-2 substrates and suggest that the C2-lacking Nedd4-2 represses excitatory synaptic strength most likely through GluA1 ubiquitination-independent mechanisms. These findings provide novel information to further our knowledge about Nedd4-2-dependent neuronal excitability homeostasis and pathological hyperexcitability when Nedd4-2 is compromised.

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“…Loss of AMPKα1 culminates in centrosome amplification and spontaneous chromosomal abnormalitiesderanged genome instability in fibroblasts. Recent studies from Li et al have uncovered a previously unrecognized function of AMPK in protecting the replication fork structure upon replication stress to ensure genome stability [51]. As AMPK is an essential modulator of cell metabolism and redox balance, it will be interesting to examine whether AMPKα1 regulates centrosome integrity-associated genomic fidelity, in part via modulating cellular redox balance.…”

Section: Discussionmentioning

confidence: 99%

Loss of AMPKalpha1 Triggers Centrosome Amplification via PLK4 Upregulation in Mouse Embryonic Fibroblasts

Zhao

Coughlan

Zou

2020

IJMS

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Recent evidence indicates that activation of adenosine monophosphate-activated protein kinase (AMPK), a highly conserved sensor and modulator of cellular energy and redox, regulates cell mitosis. However, the underlying molecular mechanisms for AMPKα subunit regulation of chromosome segregation remain poorly understood. This study aimed to ascertain if AMPKα1 deletion contributes to chromosome missegregation by elevating Polo-like kinase 4 (PLK4) expression. Centrosome proteins and aneuploidy were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J) or AMPKα1 homozygous deficient (AMPKα1−/−) mice by Western blotting and metaphase chromosome spread. Deletion of AMPKα1, the predominant AMPKα isoform in immortalized MEFs, led to centrosome amplification and chromosome missegregation, as well as the consequent aneuploidy (34–66%) and micronucleus. Furthermore, AMPKα1 null cells exhibited a significant induction of PLK4. Knockdown of nuclear factor kappa B2/p52 ameliorated the PLK4 elevation in AMPKα1-deleted MEFs. Finally, PLK4 inhibition by Centrinone reversed centrosome amplification of AMPKα1-deleted MEFs. Taken together, our results suggest that AMPKα1 plays a fundamental role in the maintenance of chromosomal integrity through the control of p52-mediated transcription of PLK4, a trigger of centriole biogenesis.

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

Cited by 68 publications

References 90 publications

DNA damage kinase signaling: checkpoint and repair at 30 years

DNA damage kinase signaling: checkpoint and repair at 30 years

C2‐lacking isoform of Nedd4‐2 regulates excitatory synaptic strength through GluA1 ubiquitination‐independent mechanisms

Loss of AMPKalpha1 Triggers Centrosome Amplification via PLK4 Upregulation in Mouse Embryonic Fibroblasts

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