Sir2 takes affirmative action to ensure equal opportunity in replication origin licensing

In all eukaryotes, chromosomal DNA replication initiates at multiple sites distributed along chromosomes called origins of replication. The initiation of DNA synthesis is a two-step process involving the loading of the minichromosome maintenance (MCM) double hexamer on origins during the G1 phase of the cell cycle and the activation of licensed origins during the S phase (1). This strict temporal separation of origin licensing from firing ensures that a given origin is activated once and only once per cell cycle, thereby preventing overreplication of the genome (Fig. 1 A ). To avoid underreplication, cells must also ensure that initiation events are evenly distributed along chromosomes. This is achieved by licensing many more origins than actually needed (2, 3). Consequently, only a fraction of potential initiation sites are activated during the S phase, the remaining ones serving as backup origins when fork progression is impeded (4, 5). Origin activation follows a defined replication timing program, in which open chromatin domains replicate early in S phase and heterochromatin replicates late (1). This sequential activation of replication origins allows a tight coordination between DNA synthesis and the production of histones and dNTPs. Moreover, the replication program can be interrupted when forks encounter DNA lesions and restarted once replication stress is relieved (6). The correct execution of the replication timing program is therefore essential to maintain the integrity of eukaryotic genomes. Fig. 1. The histone deacetylase Sir2 dampens the activity of early origins to favor an equal distribution of initiation events throughout the budding yeast genome. ( A ) The activation of replication origins in budding yeast depends on the binding of the origin recognition complex (ORC) to autonomous replicating sequences (ARS) and the loading of Mcm2-7 double hexamers in a Cdc6- and Cdt1-dependent manner to form the prereplication complex (pre-RC). Although ORC is bound to origins … [↵][1]1To whom correspondence may be addressed. Email: ppasero{at}igh.cnrs.fr. [1]: #xref-corresp-1-1