Human cell stained with a marker for SON (red; left image) and SRRM2/SC35 (green; center image) highlights where nuclear speckles are located (right image) in relation to the cell’s DNA (blue). Image credit: Ibrahim Ilik (CC BY 4.0)
Most cells store their genetic material inside a compartment called the nucleus, which helps to separate DNA from other molecules in the cell. Inside the nucleus, DNA is tightly packed together with proteins that can read the cell’s genetic code and convert into the RNA molecules needed to build proteins. However, the contents of the nucleus are not randomly arranged, and these proteins are often clustered into specialized areas where they perform their designated roles.
One of the first nuclear territories to be identified were granular looking structures named Nuclear Speckles (or NS for short), which are thought to help process RNA before it leaves the nucleus. Structures like NS often contain a number of different factors held together by a core group of proteins known as a scaffold. Although NS were discovered over a century ago, little is known about their scaffold proteins, making it difficult to understand the precise role of these speckles.
Typically, researchers visualize NS using a substance called SC35 which targets specific sites in these structures. However, it was unclear which parts of the NS this marker binds to. To answer this question, Ilik et al. studied NS in human cells grown in the lab. The analysis revealed that SC35 attaches to certain parts of a large, flexible protein called SRRM2. Ilik et al. discovered that although the structure and sequence of SRMM2 varies between different animal species, a small region of this protein remained unchanged throughout evolution.
Studying the evolutionary history of SRRM2 led to the identification of another protein with similar properties called SON. Ilik et al. found that depleting SON and SRRM2 from human cells caused other proteins associated with the NS to diffuse away from their territories and become dispersed within the nucleus. This suggests that SRMM2 and SON make up the scaffold that holds the proteins in NS together.
Nuclear speckles have been associated with certain viral infections, and seem to help prevent the onset of diseases such as Huntington’s and spinocerebellar ataxia. These newly discovered core proteins could therefore further our understanding of the role NS play in disease.
