Related Experiment Video

Updated: Aug 14, 2025

Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
14:32

Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates

Published on: February 27, 2016

8.3K

SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition

Xiaomei Zhu1,2, Qunshu Su1, Haiyuan Xie1

  • 1Department of Cell Biology, and Department of General Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Nature Chemical Biology
|January 12, 2023
PubMed

Insights

WEE1 kinase activity is regulated by acetylation at Lys177, controlled by DNA damage response and SIRT1. SIRT1 deficiency leads to WEE1 activation and resistance to WEE1 inhibitors in cancer.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Cell Cycle Regulation

Background:

  • WEE1 (Wee1-like protein kinase) is a key regulator of the cell cycle and a promising cancer therapeutic target.
  • Understanding WEE1 regulation and identifying predictive biomarkers for WEE1 inhibitors are crucial for effective cancer treatment.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of WEE1 catalytic activity.
  • To identify biomarkers for predicting patient response to WEE1 inhibitors.

Main Methods:

  • Investigated the role of a conserved segment and Lys177 residue in WEE1 regulation.
  • Utilized DNA damage induction, phosphorylation (CHK1), acetylation (GCN5), and deacetylation (SIRT1) assays.
  • Assessed the impact of SIRT1 deficiency on WEE1 activity and inhibitor sensitivity.

Main Results:

  • Identified an inhibitory segment interacting with the WEE1 kinase domain via Lys177.
  • DNA damage triggers CHK1-dependent phosphorylation and GCN5-mediated acetylation at Lys177, activating WEE1.
  • SIRT1 deacetylates and inhibits WEE1; SIRT1 deficiency causes WEE1 hyperactivation and resistance to WEE1 inhibitors.

Conclusions:

  • WEE1 activity is tightly regulated by phosphorylation and acetylation, involving CHK1, GCN5, and SIRT1.
  • SIRT1 expression and WEE1 Lys177 acetylation levels are potential biomarkers for predicting sensitivity or resistance to WEE1 inhibitors in cancer therapy.

More Related Videos

Live-imaging of Breast Epithelial Cell Migration After the Transient Depletion of TIP6008:13

Live-imaging of Breast Epithelial Cell Migration After the Transient Depletion of TIP60

Published on: December 7, 2017

6.9K
In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones11:36

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones

Published on: July 25, 2019

10.8K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.8K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.5K
Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
14.8K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.7K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.9K