Related Experiment Video

Updated: Oct 24, 2025

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
11:36

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones

Published on: July 25, 2019

11.0K

Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes

Zixi Wang1, Kenian Chen2, Yuemeng Jia1

  • 1Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Nature Cancer
|August 13, 2021
PubMed

Insights

Loss of ARID1A and ARID1B proteins, key components of SWI/SNF chromatin remodelers, drives aggressive cancer by disrupting cell differentiation and proliferation. This suggests caution with therapies targeting paralogs in ARID1-mutant cancers.

Area of Science:

  • Molecular biology
  • Cancer research
  • Chromatin remodeling

Background:

  • SWI/SNF chromatin remodelers are crucial for development and cancer.
  • ARID1A and ARID1B are canonical cBAF-specific paralogs with potential synthetic lethality.
  • Simultaneous ARID1A/ARID1B mutations are common in human cancers.

Purpose of the Study:

  • To investigate the physiological and biochemical effects of combined ARID1A and ARID1B loss.
  • To understand the mechanisms by which cBAF complex abrogation leads to cancer.
  • To determine the impact of ARID1 scaffolding loss on cancer progression.

Main Methods:

  • Generation of double knockout models in mouse liver and skin.
  • Analysis of ARID1A/ARID1B loss in endometrial cancer models.
  • Biochemical characterization of residual SWI/SNF complexes.
  • Correlation of cancer mutations in ARID1 proteins with complex disassembly.

Main Results:

  • ARID1A/ARID1B loss in liver and skin induced aggressive carcinogenesis, dedifferentiation, and hyperproliferation.
  • Restoration of either ARID1A or ARID1B in double mutant endometrial cancer triggered senescence.
  • Loss of ARID1 scaffolding disrupted the function of polybromo-containing pBAF complexes.
  • 37 out of 69 cancer-associated mutations in ARID1 scaffolding domains led to complex disassembly.

Conclusions:

  • ARID1-deficient, cBAF-deficient states promote carcinogenesis across multiple tissues.
  • The findings highlight the critical role of ARID1 proteins as scaffolds in maintaining cBAF integrity and function.
  • Therapeutic strategies targeting paralogs in ARID1-mutant cancers may require careful consideration due to complex interplay and potential adverse effects.

More Related Videos

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells06:44

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

Published on: March 1, 2024

1.3K
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.2K

Related Concept Videos

DNA Damage can Stall the Cell Cycle02:37

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.6K
DNA Damage Can Stall the Cell Cycle02:37

DNA Damage Can Stall the Cell Cycle

2.8K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.7K
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.3K
Long-patch Base Excision Repair01:02

Long-patch Base Excision Repair

Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
7.3K
Base Excision Repair01:54

Base Excision Repair

One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
The first step of...
23.9K