The Blow Lab
CR-UK Chromosome Replication Research Group
University of DundeeGeneral/Lab Phone: (+44) (0)1382-385811
General/Lab Fax: (+44) (0)1382-388072
Blow, J Julian
In order for cell division to produce two daughter cells that inherit a perfect copy of the genetic material originally present in the mother cell, two difficult tasks must be accomplished: the chromosomal DNA must first be precisely duplicated, with no errors, deletions or duplications, and then the two copies must be precisely segregated to the two daughter cells. The accuracy of these events is particularly crucial to multicellular organisms, where any changes to the genome could potentially give rise to cancers which threaten the life of the entire organism. The replication licensing system plays a fundamental role in preventing sections of chromosomal DNA from replicating more than once in a single cell cycle. Origin licensing comprises the ordered chromatin loading of the Origin Recognition Complex (ORC), Cdc6, Cdt1 and finally the Mcm2-7 complex (the probable replicative helicase) onto origins of replication. Origin licensing can only occur during late mitosis and early G1. Once a licensed origin initiates in S phase, the Mcm2-7 complex travels ahead of the fork, unwinding the DNA to allow access by the replication machinery, thereby leaving behind an unlicensed replication origin. During S phase, two protein kinases - cyclin-dependent kinases (CDKs) and the Cdc7 kinase - act on licensed origins to initiate a pair of replication forks. This involves the recruitment to chromatin of a range of replication fork proteins, including Cdc45 and the GINS complex which activate Mcm2-7 as a DNA helicase to drive progression of the replication fork.
Some current research projects: Origin licensing and its regulation Dormant origins and the response to replicative stress Proteomic analysis of chromatin-associated proteins during the cell cycle Regulation of replication factories in normal and cancer cells