Abstract
Replicating the entire genome is one of the most complex tasks for all organisms. Research carried out in the last few years has provided us with a clearer picture on how cells preserve genomic information from the numerous insults that may endanger its stability. Different DNA repair pathways, coping with exogenous or endogenous threat, have been dissected at the molecular level. More recently, there has been an increasing interest towards intrinsic obstacles to genome replication, paving the way to a novel view on genomic stability. Indeed, in some cases, the movement of the replication fork can be hindered by the presence of stable DNA: RNA hybrids (R-loops), the folding of G-rich sequences into G-quadruplex structures (G4s) or repetitive elements present at Common Fragile Sites (CFS). Although differing in their nature and in the way they affect the replication fork, all of these obstacles are a source of replication stress. Replication stress is one of the main hallmarks of cancer and its prevention is becoming increasingly important as a target for future chemotherapeutics. Here we will try to summarize how these three obstacles are generated and how the cells handle replication stress upon their encounter. Finally, we will consider their role in cancer and their exploitation in current chemotherapeutic approaches.
Highlights
Replication of the genome requires the coordination of highly dynamic mechanisms
DNA polymerases have a pivotal role in the synthesis of nascent DNA strands, numerous other factors finely regulate the dynamics of the fork
DNA: RNA hybrids accumulate at FRA16D, when FANCD2 is absent, causing replication stress that is relieved by the overexpression of RNase H1 [61]
Summary
Replication of the genome requires the coordination of highly dynamic mechanisms. During this process, DNA helicases unwind the parental DNA while DNA polymerases synthesize the new daughter strands. Despite saving cells from more severe outcomes, this pathway can be highly mutagenic and it is responsible for the generation of insertions, deletions and point mutations All of these repair pathways can work outside of the S phase and try to prevent the presence of DNA lesions at the arrival of the replication fork. Y-family polymerases possess a wider catalytic site, can accommodate such a template and bypass the lesion in a pathway called translesion synthesis [6] These alternative polymerases are recruited at the level of the damage through Proliferating Cell Nuclear Antigen (PCNA) ubiquitylation that controls a regulated switch between the replicative and the Y-family polymerases. For these reasons it becomes crucial to dissect those pathways that control DNA replication dynamics providing new promising lines of therapeutics to treat cancer
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