Dynamics of Replication Origin Over-activation

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jun 9

PMID 34103496

Citations 18

Authors

Haiqing Fu

Christophe E Redon

Bhushan L Thakur

Koichi Utani

Robin Sebastian

Sang-Min Jang

Jacob M Gross

Sara Mosavarpour

Anna B Marks

Sophie Z Zhuang

Sarah B Lazar

Mishal Rao

Shira T Mencer

Adrian M Baris

Lorinc S Pongor

Mirit I Aladjem

Affiliations

Soon will be listed here.

Abstract

Safeguards against excess DNA replication are often dysregulated in cancer, and driving cancer cells towards over-replication is a promising therapeutic strategy. We determined DNA synthesis patterns in cancer cells undergoing partial genome re-replication due to perturbed regulatory interactions (re-replicating cells). These cells exhibited slow replication, increased frequency of replication initiation events, and a skewed initiation pattern that preferentially reactivated early-replicating origins. Unlike in cells exposed to replication stress, which activated a novel group of hitherto unutilized (dormant) replication origins, the preferred re-replicating origins arose from the same pool of potential origins as those activated during normal growth. Mechanistically, the skewed initiation pattern reflected a disproportionate distribution of pre-replication complexes on distinct regions of licensed chromatin prior to replication. This distinct pattern suggests that circumventing the strong inhibitory interactions that normally prevent excess DNA synthesis can occur via at least two pathways, each activating a distinct set of replication origins.

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