Dormant origins, the licensing checkpoint, and the response to replicative stresses

McIntosh, Debbie and Blow, J. Julian ORCID: https://orcid.org/0000-0002-9524-5849 (2012) Dormant origins, the licensing checkpoint, and the response to replicative stresses. Cold Spring Harbor Perspectives in Biology, 4 (10). ISSN 1943-0264

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Abstract

Only ~10% of replication origins that are licensed by loading minichromosome maintenance 2-7 (MCM2-7) complexes are normally used, with the majority remaining dormant. If replication fork progression is inhibited, nearby dormant origins initiate to ensure that all of the chromosomal DNA is replicated. At the same time, DNA damage-response kinases are activated, which preferentially suppress the assembly of new replication factories. This diverts initiation events away from completely new areas of the genome toward regions experiencing replicative stress. Mice hypomorphic for MCM2-7, which activate fewer dormant origins in response to replication inhibition, are cancer-prone and are genetically unstable. The licensing checkpoint delays entry into S phase if an insufficient number of origins have been licensed. In contrast, humans with Meier-Gorlin syndrome have mutations in pre-RC proteins and show defects in cell proliferation that may be a consequence of chronic activation of the licensing checkpoint.

Item Type:	Article
Uncontrolled Keywords:	factory activation,meier-gorlin syndrome,primordial dwarfism,tumor suppression,mammalian-cells,eukaryotic dna-replication,s-phase checkpoint,recognition complex,human-cells,xenopus egg extracts,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:
Depositing User:	LivePure Connector
Date Deposited:	10 Jun 2024 15:31
Last Modified:	25 Sep 2024 17:53
URI:	https://ueaeprints.uea.ac.uk/id/eprint/95486
DOI:	10.1101/cshperspect.a012955

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