The Blow Lab:

Dormant Replication Origins

We have recently shown that for each origin that actually fires during an unperturbed S phase (a ‘primary’ origin) there are approximately 3-10 origins that are not used (‘dormant’ origins). These dormant origins are normally kept in check by checkpoint kinases, but become necessary for the complete replication of DNA when replication fork progress is inhibited. We are currently investigating how the usage of primary and dormant origins is regulated. We are investigating the physical relationship between ORC binding sites, primary origins and dormant origins. We are also investigating the mechanisms that regulate the use of dormant origins. Computer modelling suggests that activation of dormant origins in response to replication fork inhibition fits very well to a ‘passive’ mechanism, where origins initiate stochastically in origin clusters. We are currently investigating mechanisms which regulate the activation of origin clusters.

Replication origins are organised into clusters that are activated at distinct times during S phase by being incorporated into replication ‘factories’. We have shown that when replication is inhibited, the predominant effect of ATR/Chk1 on S phase is to inhibit activation of new replication factories. The net result is to divert new initiation away from completely unreplicated regions of the genome and to activate dormant origins in regions of the genome currently experiencing replicative stress. We are currently investigating the mechanisms by which replication factory activation is regulated. Certain cancer cell lines show defects in their ability to regulate replication factories in response to replicative stresses. Since many chemotherapeutic drugs cause replicative stress, this work will yield fundamental information about how cells respond to these drugs.

     Woodward, A.M, Göhler, T. Luciani, M.G., Oehlmann, M., Ge, X., Gartner, A., Jackson, D.A. and Blow, J.J. (2006). Excess Mcm2-7 license dormant origins of replication for use when replication fork progress is inhibited. J. Cell Biol. 173, 673-683. [Faculty of 1000 Recommendation] [abstract]

     Ge, X.Q., Jackson, D.A. and Blow, J.J. (2007). Dormant origins are required for human cells to survive replicative stress. Genes Dev. 21, 3331-3341. [abstract]

     Blow, J.J. and Ge, X.Q. (2009). A model for DNA replication showing how inefficient origins safeguard against fork failure. EMBO Rep 10, 406-412.  [abstract]

     Ge, X.Q. and Blow, J.J. (2010). Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories. J Cell Biol 191, 1285–1297. [abstract]

     Klotz-Noack, K. and Blow, J.J. (2011). A role for dormant origins in tumour suppression. Mol. Cell 41, 495-496. [abstract]

     Blow, J.J., Ge, X.Q. and Jackson, D.A. (2011). How dormant origins promote complete genome replication. Trends Biochem Sci. 6, 405-414. [abstract]

Saner, N., Karschau, J., Natsume, T., Gierliński, M., Retkute, R., Hawkins, M., Nieduszynski, C.A., Blow, J.J., de Moura, A.P.S. and Tanaka, T.U. (2013). Stochastic association of neighboring replicons creates replication factories in budding yeast. J. Cell Biol. 202, 1001-1012. [abstract] [pdf]

Alver, R.C., Singh Chadha, S. and Blow, J.J. (2014). The contribution of dormant origins to genome stability: from cell biology to human genetics. DNA Repair 19, 182-189. [abstract] [pdf]