Selective interactions at pre-replication complexes categorize baseline and dormant origins

The initiation of DNA synthesis in metazoans is restricted to a group of baseline replication origins, whereas other (dormant) origins do not initiate replication despite recruiting apparently indistinguishable pre-replication complexes. Dormant origins are activated as backups when DNA synthesis stalls. We report that dormant origins selectively bind CDK-phosphorylated RecQL4 (pRecQL4), a helicase mutated in Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. In unperturbed cells, pRecQL4 restricts replication initiation to baseline origins by preventing dormant origins from binding the essential initiation factor MTBP. When cells encounter replication stress, pRecQL4 first promotes the dissociation of MTBP from chromatin, and then enables its redistribution to both baseline and dormant origins, facilitating compensatory initiation to complete genome duplication. Thus, MTBP-pRecQL4 interactions modulate replication origin choice and facilitate recovery from replication stress.