18 Responses to Aberrant DNA Replication and DNA Damage in Metazoa

Abstract

The transmission of genetic information from one cell generation to the next requires the faithful, timely, and complete duplication of the genetic material during the process of DNA replication (Kelly and Brown 2000; Bell and Dutta 2002). The mechanisms regulating these processes are directly responsible for maintaining the integrity of the genome and the characteristic ploidy of every organism.

Cells are constantly subjected to DNA lesions and have developed a complex set of responses collectively named DNA damage response (Zhou and Elledge 2000). The physiological outputs of these signaling pathways are cell-cycle arrest, DNA repair, and apoptosis. Cell-cycle checkpoints are the pathways relaying signals triggered by aberrant DNA structures that ultimately prevent or slow down cell-cycle progression. These signaling pathways have been operationally divided into sensing, transducing, and effector steps, a nomenclature emphasizing the linear nature of these pathways. However, checkpoint pathways are not strictly linear. Several regulators of the response to DNA damage play multiple roles at different steps of these pathways. Moreover, regulatory feedback loops are also modulating the cell-cycle response to DNA damage checkpoint pathways.

Because of the complexity of the reactions occurring during DNA replication, genome integrity is constantly challenged during S phase (Bartek et al. 2004). Therefore, the decision to start DNA replication, i.e., the firing of a replication origin, is tightly regulated and under the control of both cell-cycle and DNA damage checkpoints signaling. During replication, the replication fork is a vulnerable structure, as it is the center of complex DNA transactions, including DNA...