ABSTRACT
The ability of cells to fully and faithfully replicate their DNA is essential for ensuring genomic integrity. Most of the genomic instability that is necessary for the development of many types of cancers can ultimately be attributed to replication problems. Although chromosome replication is a remarkably accurate process, DNA replication is potentially dangerous by itself and can be cause of DNA damage. Singleand double-strand breaks (DSBs) continuously arise due to the action of nick and closing enzymes (i.e., DNA topoisomerases) and DNA replication can be perturbed by intrinsic replication errors that can arise from nucleotide misincorporation, availability of nucleotide pools and from slippage of newly synthesized DNA on repetitive DNA sequences (1-3). Replication errors can have important consequences as they can result in the joining of sequences with very little homology, thus causing deletions or expansions of repeated sequences (4). Furthermore, the intrinsic difficulty of certain DNA regions to be replicated may cause chromosome breakage and the expression of fragile sites, specific regions in the human genome particularly prone to rearrangements and deletions (5). Finally, eukaryotic chromosomes are linear DNA molecules, which represent a dilemma for their complete replication. The ability of all known DNA polymerases to proceed only in the 50-30 direction with each newly synthesized DNA molecule being RNA primed poses a problem for synthesizing DNA at the end of a linear replicon. In fact, while the leading strand acts as a template to synthesize a daughter strand that runs right up to the end, removal of the most distal RNA primer in the complementary strand leaves an 8-to 12-base gap at the 50 end that cannot be repaired by conventional enzymes (6,7).
