ABSTRACT
Tolerance to replication-blocking lesions in the DNA is of vital importance for a cell’s resistance to genotoxic agents. Within double-stranded (ds) DNA, excision repair systems efficiently remove various types of damage to bases and nucleotides, and the information encoded by the complementary strand is used to correctly restore the original information (1). In single-stranded (ss) DNA regions, however, which arise during the duplication of the genome, these repair systems cannot operate due to the absence of an instructive template. As a consequence, unrepaired lesions act as ‘‘road blocks’’ for the replication machinery during S phase, because the active sites of replicative DNA polymerases, streamlined for accurate and processive DNA synthesis, do not accommodate distorted template structures (2,3). It is generally believed that this situation poses a minor problem on the lagging strand, where DNA replication can in principle resume by the initiation of a new Okazaki fragment, leaving a small gap opposite the damaged site. On the other hand, a blocked polymerase on the leading strand causes a permanent stalling of the replication fork, which would elicit a checkpoint response leading to cell cycle arrest and ultimately cell death if the lesion could not be circumvented or passed.
