ena-STUDY-TU Kaiserslautern-15-05-2020-08:45:51:404-269
Haploinsufficiency of ribosomal genes limits the viability of monosomic human cells by activation of the p53 pathway
Chromosome loss that results in monosomy has detrimental consequences for human cells, but the underlying molecular mechanisms remain enigmatic. Using p53 deficient monosomic cell lines, we found that chromosome loss impairs proliferation and genomic stability. Transcriptome and proteome analysis revealed a partial compensation of the gene dosage changes that mitigates the effects of chromosome loss. Monosomy triggers global gene expression changes that differ from the effects of trisomy. Strikingly, ribosome biogenesis and translation were commonly downregulated in monosomic cells. Polysome profiling and translation analysis suggest that the defects arise due to haploinsufficiency of ribosomal genes. The ensuing ribosome biogenesis stress triggers the p53 pathway and G1 arrest when TP53 is reintroduced into monosomic cells. Accordingly, impaired ribosome biogenesis and p53 inactivation are associated with monosomy in cancer. Our first systematic study of monosomy in human cells demonstrates that haploinsufficiency of ribosomal genes presents a dominant negative phenotype of monosomy.
Chromosome loss that results in monosomy has detrimental consequences for human cells, but the underlying molecular mechanisms remain enigmatic. Using p53 deficient monosomic cell lines, we found that chromosome loss impairs proliferation and genomic stability. Transcriptome and proteome analysis revealed a partial compensation of the gene dosage changes that mitigates the effects of chromosome loss. Monosomy triggers global gene expression changes that differ from the effects of trisomy. Strikingly, ribosome biogenesis and translation were commonly downregulated in monosomic cells. Polysome profiling and translation analysis suggest that the defects arise due to haploinsufficiency of ribosomal genes. The ensuing ribosome biogenesis stress triggers the p53 pathway and G1 arrest when TP53 is reintroduced into monosomic cells. Accordingly, impaired ribosome biogenesis and p53 inactivation are associated with monosomy in cancer. Our first systematic study of monosomy in human cells demonstrates that haploinsufficiency of ribosomal genes presents a dominant negative phenotype of monosomy.