Organisms and cells age and eventually die. However, germline cells, the only cell type that passes the genome to the next generation as eggs and sperm, have continued to exist through the 1.5 billion years of multicellular organisms’ history. Exactly what molecular changes constitute age and how the germline can avoid aging to ensure its continued existence remain one of the biggest mysteries in biology. The mechanisms that support the continued proliferation of germline, i.e. ‘germline immortality’ are poorly understood.
This proposal is based on our recent discoveries that began to reveal the importance of ribosomal DNA (rDNA) in germline immortality: we propose that rDNA copy number is a heritable aging factor, decreasing with age and being transmitted to the offspring. rDNA, which encodes components of the ribosome (molecular machine that supports cells’ protein synthesis), exists as arrays of repeats in the genome with hundreds and thousands of copies tandemly repeated. Although essential for cells’ survival, rDNA’s repetitiveness makes it susceptible to spontaneous copy number loss. Critically, to avoid the continued decline of rDNA copy number, the germline is uniquely equipped to restore the copy number, thus reversing the aging of the genome. This process may be compromised in aging (and early onset aging diseases) and maladapted by cancer cells.
We propose to investigate the mechanism of rDNA copy number maintenance, building upon two lines of surprising discoveries made in our laboratory: 1) an unexpected mode of chromosome segregation that distinguishes two sister chromatids (which have been believed to be identical) based on rDNA copy number difference, and 2) surprising role of a retrotransposon (believed to be ‘genomic parasites’) in rDNA copy number maintenance. Our work will provide critical insights into the very existence of multicellular organisms, and also will point to the causes and potential treatments of aging and cancer.