Importance of DNA repair in tumor suppression

Abstract

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 are fundamental to the progression of a tumor cell and hence these mechanisms act as a method for prevention and destruction of cancerous genomes.

Examining The Theory of Error Catastrophe

“…Subsequent elaborations on the model have retained the basic premise that further errors do not affect the replication of mutants (2,3,21,42,43,44,45 Empirical evidence for error catastrophe. Despite the absence of any realistic theoretical underpinning, error catastrophe claims experimental support from two general types of observation in the literature: (i) loss of virus infectivity from cell cultures after serial passage in the presence of a mutagen and (ii) an apparent threshold mutation frequency for infectivity of viruses or viral RNAs.…”

“…Eigen and Schuster referred to this hypothetical redistribution of the genetic information of the system as an error catastrophe (not to be confused with the theory of ageing that is also called error catastrophe [30,31,32]). Various treatments of the basic model have appeared in the literature since publication of Eigen and Schuster's original paper (2,3,21,42,42,44,45).…”

Protein stability imposes limits on organism complexity and speed of molecular evolution

“…In most viruses such as the HIV retrovirus, mutations and replication are decoupled, and parent genomes are not preserved as mutations are introduced, e.g., mostly at the reverse-transcription stage, after which original parent RNA is degraded. In bacteria, replication is semiconservative, i.e., mutations can be introduced in either strand by the action of an error-correction mechanism (35,37), so that both progenies may carry mutations after replication, again eliminating the preservation of the parent genome.…”

Evolutionary dynamics of adult stem cells: Comparison of random and immortal-strand segregation mechanisms

“…In particular, we develop an ordered strand pair formulation of the dynamics, analogous to the ordered strand pair formulation of the quasispecies equations for semiconservative replication with imperfect lesion repair [5,6,7]. For random segregation, the equations derived are similar to the corresponding quasispecies equations.…”

“…Immortal strand co-segregation can only provide an advantage, however, if, during a process known as lesion repair, not all postreplication DNA mismatches are corrected Otherwise, daughter-strand synthesis errors can become fixed as mutations in both parent and daughter strands, thereby eliminating the advantage of keeping the oldest template strand in the stem cell [4,5,6,7].…”