Aneuploidy alleviates the cell proliferation defect caused by mutations affecting origin licensing in Saccharomyces cerevisiae

Although aneuploidy is generally detrimental to the survival and growth of normal cells, it can be beneficial under certain stress conditions, such as those caused by harmful mutations. In Saccharomyces cerevisiae, we find that duplication of chromosome III accelerates cell proliferation in the orc5–1 mutant. Enhanced proliferation is also observed when a fragment from a different chromosome is introduced, demonstrating that the benefit is not simply due to extra copies of specific genes. A comparable growth-enhancing effect of an extra chromosome is observed for mutations affecting other proteins involved in DNA replication licensing. The suppression of orc5–1 growth defect is also observed in the absence of the G1 cyclin Cln3, which lengthens the G1 phase, while overexpressing CLN3, which shortens G1, has the opposite effect. Additionally, Cln3 loss mirrors the effect of an extra chromosome for other mutations. These findings indicate that the severity of mutations impacting origin licensing hinges on the length of the G1 phase. Thus, we propose that the fitness-enhancing effect of an extra chromosome in DNA replication licensing mutants largely stems from its ability to extend G1, compensating for inefficient origin licensing.Author summary: While having the wrong number of chromosomes, known as aneuploidy, is usually detrimental to cells, it can sometimes promote survival under stressful conditions, such as those arising from certain genetic mutations. Using the yeast model Saccharomyces cerevisiae, we discovered that an extra copy of chromosome III enhances the growth of a mutant strain with defects in DNA replication licensing. This growth advantage does not rely on specific genes located on chromosome III, as a different chromosomal fragment confers a similar benefit. We also found that prolonging the G1 phase of the cell cycle, a common consequence of aneuploidy, by deleting the cell cycle regulator Cln3, similarly supports growth in these mutants. Our finding suggests that the fitness advantage provided by aneuploidy in replication licensing mutants primarily stems from the extended G1 phase, which gives additional time for the preparation of DNA replication when origin licensing is compromised.