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Dormant Origins, the Licensing Checkpoint, and the Response to Replicative Stresses

Dormant Origins, the Licensing Checkpoint, and the Response to Replicative Stresses

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Original languageEnglish
Article number012955
Number of pages10
JournalCold spring harbor perspectives in biology
Journal publication dateOct 2012
Volume4
Issue10
DOIs
StatePublished

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.

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