Grant: Operating Grant

Centromeres are structures on chromosomes that are essential for the proper separation of the DNA during cell division, acting as a molecular handle for the cell to latch onto and pull chromosomes apart. Defects in centromeres lead to inequities in the division of chromosomes, and result in the inheritance of too few or too many genes in daughter cells. Having too much or too little DNA underlies diseases such as cancer, leads to genetic disorders such as Down syndrome, and impacts overall fertility. Thus, understanding how centromeres are built and controlled is critical for devising treatments or preventative measures for such conditions. One newly discovered cellular mechanism for regulating centromeres is executed by tiny RNA molecules, known as small RNAs. Small RNAs normally play key roles in regulating gene expression during development, and in combating cellular invaders such as viruses. The notion that small RNAs influence the construction of centromeres in animals opens a new and exciting field of study, and leads to a more complete understanding of how centromeres are regulated. We will use the soil nematode, C. elegans, to uncover the functions of particular small RNA pathways in organizing centromeres and properly separating chromosomes. C. elegans is a well-established research model, possessing many of the same key tissue types and cellular functions as humans. Many important advances in understanding other small RNA mechanisms initially were made using C. elegans, and subsequently were found to extend to humans. Thus, the worm provides an ideal context in which to study small RNA pathways. Because properly building and separating chromosomes ensures the appropriate transmission of DNA to new cells and prevents mutations, understanding how small RNA pathways regulate such processes provides key insights into fertility, normal human development, cancer emergence, and ideally could lead to new therapeutic agents.