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

TY - JOUR

T1 - Dormant Origins, the Licensing Checkpoint, and the Response to Replicative Stresses

A1 - McIntosh,Debbie

A1 - Blow,J. Julian

AU - McIntosh,Debbie

AU - Blow,J. Julian

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

KW - FACTORY ACTIVATION

KW - MEIER-GORLIN SYNDROME

KW - PRIMORDIAL DWARFISM

KW - TUMOR SUPPRESSION

KW - MAMMALIAN-CELLS

KW - EUKARYOTIC DNA-REPLICATION

KW - S-PHASE CHECKPOINT

KW - RECOGNITION COMPLEX

KW - HUMAN-CELLS

KW - XENOPUS EGG EXTRACTS

U2 - 10.1101/cshperspect.a012955

DO - 10.1101/cshperspect.a012955

M1 - Article

JO - Cold spring harbor perspectives in biology

JF - Cold spring harbor perspectives in biology

SN - 1943-0264

IS - 10

VL - 4

ER -