Open sesame: activating dormant replication origins in the mouse immunoglobulin heavy chain (Igh) locus

Chromosomal DNA replication in mammals initiates from replication origins whose activity differs in accordance with cell type and differentiation state. In addition to origins that are active in unperturbed conditions, chromosomes also contain dormant origins that can become functional in response to certain genotoxic stress conditions. Improper regulation of origin usage can cause genomic instability leading to tumorigenesis. We review findings from recent single-molecule DNA fiber studies examining replication of the mouse immunoglobulin heavy chain (Igh) locus, in which origin activity over a 400kb region is subject to dramatic developmental regulation. Possible models are discussed to explain such differential origin usage, particularly during replication stress conditions that can activate dormant origins.