Human acrocentric chromosomes, nucleolar formation and rDNA genomic stability

Nucleoli, sites of ribosome biogenesis and the largest structures in the human nucleus, form around nucleolar organiser regions (NORs) located on the short or p-arms of five different chromosomes referred to as acrocentric chromosomes. NORs comprise ribosomal genes (rDNA) arrays coding for the major RNA components of ribosomes. How multiple acrocentric p-arms gather together to form a nucleolus and how NORs partition within nucleoli are important but unanswered questions. Progress has been hampered by the inability to distinguish acrocentric p-arms from each other due to their shared DNA-sequences. To circumvent this impasse, we perform chromosome-engineering on single human chromosomes held in mouse cells, then reintroduce them into human cells to test function in nucleolar formation. Using this transformative technology we will address the above questions and explore tantalising links between rDNA genome-stability and cell-ageing. This work has added significance as nucleoli represent an important paradigm for understanding human genome organisation.