In our cells, a vast amount of genetic information is stored in DNA. To manage this library, cells use molecular machines that act like librarians, organizing and providing access to specific genetic chapters. The INO80 complex is one such machine, an ATP-dependent chromatin remodeler. Its function is to navigate tightly packaged DNA, adjusting its structure to allow cellular machinery to read, copy, or repair the genetic code, ensuring the right information is available when needed.
Composition and Structure of the INO80 Complex
The INO80 complex is a large assembly of at least 15 distinct protein subunits. At its heart is the main Ino80 subunit, which contains a specialized motor domain known as an ATPase. This engine is part of the Swi2/Snf2 family of proteins and provides energy for the complex’s activities by breaking down ATP. This core ATPase is evolutionarily conserved from yeast to humans, highlighting its important role.
Surrounding this central engine are modules of accessory subunits that provide structure and specificity. One feature is a ring-shaped structure formed by the Rvb1 and Rvb2 proteins, necessary for the assembly and activity of the complex. Another module contains actin and several actin-related proteins (Arps), specifically Arp4, Arp5, and Arp8. These Arp subunits help the complex recognize and bind to both DNA and the nucleosome structures it modifies. Other subunits, like the Nhp10 module, help stabilize the complex and guide it to specific locations on the genome.
The Mechanism of Chromatin Remodeling
To understand how the INO80 complex works, it is helpful to know how DNA is packaged. The immense length of DNA is condensed by wrapping it around spool-like proteins called histones. A segment of DNA wrapped around a core of eight histone proteins forms a nucleosome, the repeating unit of chromatin. This packaging compacts the DNA and creates a physical barrier, blocking access to the genetic information it contains.
The primary job of the INO80 complex is to physically reposition these nucleosomes, a process called “nucleosome sliding.” The complex binds to DNA near a nucleosome and uses energy from its motor subunit to pull the DNA around the histone core. This action slides the histone octamer along the DNA strand to a new position. This movement can expose a previously covered segment of DNA or hide a previously accessible one.
The process is regulated and depends on the nucleosome and surrounding DNA. The INO80 complex requires a certain length of accessible DNA next to a nucleosome, known as linker DNA, to initiate sliding. For instance, it needs a specific length of this linker DNA to work efficiently. Subunits like Arp8 and Arp5 are thought to act as sensors, gripping both the linker DNA and the nucleosome to facilitate the controlled movement.
Key Cellular Functions
The act of sliding nucleosomes enables the INO80 complex to participate in several cellular processes. By adjusting DNA accessibility, it influences when and how the genetic blueprint is used. These functions connect the physical movement of nucleosomes to biological outcomes that maintain cellular health.
One of the most studied roles of the INO80 complex is in DNA repair. When DNA is damaged, repair machinery needs to access the broken site. INO80 is recruited to the location of damage, where it repositions nucleosomes to clear the area for repair proteins to mend the DNA. Its involvement is also noted in transcription regulation, where it can slide nucleosomes away from a gene’s promoter region, allowing machinery to read the gene and turn it “on.”
The complex also has a function in DNA replication. Before a cell divides, its genome must be accurately copied, but the path of replication machinery can be obstructed by nucleosomes. The INO80 complex helps clear this path, facilitating the smooth progression of the replication fork and ensuring the complete duplication of the genome. The core function in all these roles is managing chromatin structure to control DNA access.
Implications in Human Health and Disease
Malfunctions in the INO80 complex are linked to human diseases. Errors in the expression or function of its subunits can disrupt DNA repair, gene regulation, and replication, leading to genomic instability—a hallmark of many disorders. This is particularly relevant in cancer, where control over cell growth and division is lost.
Elevated expression of INO80 is observed in several types of cancer, including lung cancer, colon cancer, and melanoma. In some cases, the complex promotes the expression of oncogenes, which are genes that can drive tumor development. Conversely, mutations causing a partial loss of INO80 function are also found in certain cancers, like rare T-cell lymphomas. This suggests that cancer cells may be sensitive to the levels of INO80 activity, creating a potential vulnerability for therapies.
Beyond cancer, the INO80 complex is implicated in developmental processes. Proper development requires orchestrated patterns of gene expression, which rely on chromatin remodelers like INO80. For example, mutations in the INO80 subunit YY1AP1 are associated with Grange syndrome, a rare developmental disorder affecting the growth of bones, blood vessels, and other tissues.