Importance of DNA repair in tumor suppression.
The transition from a normal to cancerous cell requires a number of highly specific mutations that affect cell cycle regulation, apoptosis, differentiation, and many other cell functions. One hallmark of cancerous genomes is genomic instability, with mutation rates far greater than those of normal cells. In microsatellite instability (MIN tumors), these are often caused by damage to mismatch repair genes, allowing further mutation of the genome and tumor progression. These mutation rates may lie near the error catastrophe found in the quasispecies model of adaptive RNA genomes, suggesting that further increasing mutation rates will destroy cancerous genomes. However, recent results have demonstrated that DNA genomes exhibit an error threshold at mutation rates far lower than their conservative counterparts. Furthermore, while the maximum viable mutation rate in conservative systems increases indefinitely with increasing master sequence fitness, the semiconservative threshold plateaus at a relatively low value. This implies a paradox, wherein inaccessible mutation rates are found in viable tumor cells. In this paper, we address this paradox, demonstrating an isomorphism between the conservatively replicating (RNA) quasispecies model and the semiconservative (DNA) model with post-methylation DNA repair mechanisms impaired. Thus, as DNA repair becomes inactivated, the maximum viable mutation rate increases smoothly to that of a conservatively replicating system on a transformed landscape, with an upper bound that is dependent on replication rates. On a specific single fitness peak landscape, the repair-free semiconservative system is shown to mimic a conservative system exactly. We postulate that inactivation of post-methylation repair mechanisms is fundamental to the progression of a tumor cell and hence these mechanisms act as a method for the prevention and destruction of cancerous genomes.
Brumer
Yisroel
Y
Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Shakhnovich
Eugene I
EI
D000818:Animals; D020137:Base Pair Mismatch / Q000235:genetics; D003198:Computer Simulation; D004249:DNA Damage / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D019143:Evolution, Molecular; D014644:Genetic Variation / Q000235:genetics; D005828:Genetics, Population; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D013489:Suppression, Genetic / Q000235:genetics*
D004273:DNA, Neoplasm