HOUSTON, NOVEMBER 24, 2025 ― Researchers at The University of Texas MD Anderson Cancer Center have shown that DNA inflexibility, or rigidity, inside the nucleosome regulates the positioning of INO80. This highlights that the physical structure and shape of DNA, not just genetic information, are key components of DNA transcription.
The study, published today in Molecular Cell , was led by Blaine Bartholomew, Ph.D. , professor of Epigenetics and Molecular Carcinogenesis , and Shagun Shukla, Ph.D.
"We have found the remarkable specificity of INO80 to position nucleosomes, the building blocks of chromatin and chromosomes, is due to being stopped by highly inflexible DNA. By taking snapshots during remodeling, we were able to identify the steps in nucleosome movement blocked by these specific regions in the genome," Bartholomew said.
Why is it important to study INO80 and know how nucleosomes are moved?
Mutations, deletions and overexpression of INO80 and its subunits are associated with heart disease and cancer. Understanding how INO80 influences DNA transcription and repair provides insights into critical processes such as gene regulation and cell differentiation. Studying INO80 and its subunits helps identify potential targets for the development of therapeutic strategies for cancer and other diseases.
What is the INO80 chromatin remodeling complex?
DNA transcription is the first step in gene expression, which is essential for building proteins. Transcription involves unwrapping tightly wound portions of DNA so that molecules can access certain genes to make copies.
The INO80 chromatin remodeling complex manages how DNA is packaged around complexes called nucleosomes, making it accessible when needed and hidden when not. Understanding how INO80 moves nucleosomes is important because it is a crucial component in cellular processes such as DNA transcription, repair and replication.
Inflexible DNA, which is normally rigid and resistant to bending due to its sequence or structure, had been thought to block INO80 from moving these nucleosomes, but had not, until now, been shown. Little was known about how this process occurs.
What did the researchers learn about INO80 in this study?
Most chromatin remodeling proteins move the nucleosomes in short lengths of one or two DNA base pairs at a time. The researchers discovered that INO80 uses a unique mechanism that displaces larger stretches of 20-30 DNA base pairs away from the core of the nucleosome, creating loops or bulges that allow it to move around the nucleosome in a wave-like manner.
The researchers found that this inflexible DNA within the nucleosome stops its movement, interfering with the formation of the loops or bulges and allowing INO80 to position itself on the surface of nucleosomes at the right location.
Interestingly, Bartholomew's lab previously showed that Arp5 – a subunit of INO80 – rotates dynamically, thereby switching the region of Arp5 contacting the nucleosome. When bound to inflexible DNA, the researchers noticed that some of those interactions of Arp5 are lost, meaning that INO80 cannot modify the nucleosome.
These findings suggest that the Arp5 subunits may act as sensors that regulate INO80 remodeling depending on the shape of the DNA.
