Related Experiment Video

Updated: Sep 8, 2025

Simple and Fast Rolling Circle Amplification-Based Detection of Topoisomerase 1 Activity in Crude Biological Samples
10:13

Simple and Fast Rolling Circle Amplification-Based Detection of Topoisomerase 1 Activity in Crude Biological Samples

Published on: December 2, 2022

2.7K

Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability

Tae-Hee Lee1, Colina X Qiao1,2,3, Vladislav Kuzin4

  • 1Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Nature Communications
|August 12, 2025
PubMed

Insights

The histone variant macroH2A1.1 prevents DNA damage by resolving topoisomerase 1 cleavage complexes (TOP1ccs). Its alternative splicing impacts genome maintenance and cancer vulnerability.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Genomics

Background:

  • DNA transactions create torsional stress, risking genome integrity.
  • Topoisomerase 1 (TOP1) resolves supercoils, but stabilized TOP1:DNA cleavage complexes (TOP1ccs) cause DNA damage.
  • Mechanisms protecting genomic hot spots from excessive TOP1cc accumulation are unknown.

Purpose of the Study:

  • To investigate the role of chromatin context in resolving TOP1ccs.
  • To identify factors that prevent excessive TOP1cc accumulation at topological stress sites.
  • To explore the link between macroH2A1 splicing, genome maintenance, and cancer.

Main Methods:

  • Investigated TOP1cc resolution in relation to chromatin context.
  • Utilized poly(ADP-ribose) (PAR) binding assays.
  • Performed pharmaco-genomic screening in breast cancer cells.

Main Results:

  • The histone variant macroH2A1.1 binds PAR and facilitates TOP1cc repair factor recruitment and turnover.
  • MacroH2A1.1 prevents DNA damage from transcription-associated topological stress.
  • The macroH2A1.2 isoform lacks PAR-binding and protective capabilities.
  • Impaired macroH2A1.1 splicing, common in cancer, correlated with increased sensitivity to TOP1 poisons.

Conclusions:

  • MacroH2A1.1 acts as a critical factor in resolving TOP1ccs via PAR binding.
  • Alternative splicing of macroH2A1 modulates TOP1-mediated genome maintenance.
  • MacroH2A1 alternative splicing represents a potential cancer vulnerability.

More Related Videos

Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications10:12

Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications

Published on: April 21, 2023

2.9K
Author Spotlight: Epigenetic Modifications and Metabolic Rewiring as Targets for Cancer Therapy07:20

Author Spotlight: Epigenetic Modifications and Metabolic Rewiring as Targets for Cancer Therapy

Published on: October 18, 2024

615

Related Concept Videos

DNA Topoisomerases02:02

DNA Topoisomerases

Topoisomerases are enzymes that relax overwound DNA molecules during various cell processes, including DNA replication and transcription. These enzymes regulate positive and negative DNA supercoiling without changing the nucleotide sequence. DNA overwinding in a clockwise direction results in positively supercoiled DNA, whereas underwinding in a counterclockwise direction produces negatively supercoiled DNA.
Types and Mechanism of action
Topoisomerases are divided into two main types. ...
31.9K
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
3.1K
Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
4.4K
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...
4.6K
Conservative Site-specific Recombination and Phase Variation02:53

Conservative Site-specific Recombination and Phase Variation

Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
The recognition sites for Cre recombinase called LoxP...
6.1K
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

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.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
5.1K