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

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.

• Authors: Debbie McIntosh, J Julian Blow
• Journal: Cold Spring Harbor perspectives in biology (Cold Spring Harb Perspect Biol) Vol. 4 Issue 10 (Oct 01 2012) ISSN: 1943-0264 [Electronic] United States
• PMID: 22904560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Cell Cycle Proteins

Topics

• Animals
• Cell Cycle Checkpoints
• Cell Cycle Proteins (metabolism, physiology)
• Congenital Microtia
• DNA Damage
• DNA Replication (physiology)
• Ear (abnormalities)
• Growth Disorders (genetics)
• Humans
• Mice
• Micrognathism (genetics)
• Models, Genetic
• Patella (abnormalities)
• Replication Origin (genetics, physiology)
• Stress, Physiological