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

Bhushan L. Thakur,Christophe E Redon,Haiqing Fu,Robin Sebastian,N. A. Kusi,Sophie Z. Zhuang,L. Pongor,V. A. Bohr,M. Aladjem

Published 2025 in Nature Communications

ABSTRACT

DNA synthesis in metazoans initiates within a select group of replication origins (baseline 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, allowing for complete genome duplication, yet it is unclear how cells selectively differentiate between baseline and dormant origins. We report here that during unperturbed cell proliferation, dormant origins selectively bind phosphorylated RecQL4 (pRecQL4), a member of the RecQ helicase family mutated in Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. Origin-bound pRecQL4 prevents the binding of an essential replication initiation complex, MTBP-TICRR/TRESLIN, to dormant origins, thus restricting replication initiation to baseline origins. When cells encounter replication stress, pRecQL4 is required for the dissociation of the MTBP-TICRR/TRESLIN complex from chromatin, which, in turn, facilitates the subsequent redistribution of MTBP-TICRR/TRESLIN to both baseline and dormant origins and allows recovery from replication inhibition. Thus, the interactions between the MTBP-TICRR/TRESLIN complex and pRecQL4 at replication origins are critical for replication origin choice and facilitate recovery from replication stress. Dormant replication origins begin DNA synthesis under replication stress and are inactive in unperturbed cells. Here, the authors show that phospho-RecQL4 helicase blocks dormant origins’ activation by the Treslin/MTBP complex, facilitating its redistribution to activate dormant origins upon stress.

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