BACR educational session – Recent breakthroughs in DNA replication field

Host: Aga Gambus, Institute for Cancer and Genomic Sciences, University of Birmingham

08:15-09:00

Room: Default Location

Cancer chromosomal instability (CIN) is observed in most solid tumours and is associated with poor prognosis and drug resistance (McGranahan et al., 2012). CIN leads to pathogenic changes in chromosomal number and structure, generating intra-tumour heterogeneity. Recent data implicate a central role for replication stress in the generation of CIN and about 66% of cancer-driving mutations are due to stochastic DNA replication errors (Burrell et al., 2013; Tomasetti et al., 2017) In prostate, brain and bone cancers, more than 95% of cancer drivers are caused by random DNA-copying errors.

Many current therapeutic approaches rely on exploiting defects in chromosomal replication often observed in tumours. However, these therapies are non-specific and generally highly toxic to normal rapidly dividing cells. A better understand into how normal and pathogenic errors in DNA replication arise will enable more accurately targeting of the aberrant cancer DNA replication machinery, and thus more selective therapeutic interventions.

The process of DNA replication has been studied intensively ever since Watson and Crick presented the DNA structure and proposed the semiconservative mode of its replication. However the last ten years and establishment of new technologies have brought a number of knowledge leaps in the replication field. During this workshop, I will present recent methodologies developed in the field, including in vitro reconstitution of DNA replication based on purified budding yeast proteins, and genome wide approaches identifying origins of replication and DNA polymerase usage. I will outline the key findings that these technologies led to, particularly in our understanding of DNA replication initiation. I will also describe the breakthroughs in understanding the final stage of DNA replication – termination. Finally, I will summarise our current understanding into how DNA replication stress impacts on development, both of an organism and cancer.

REFERENCES
Burrell, R.A., McClelland, S.E., Endesfelder, D., Groth, P., Weller, M.C., Shaikh, N., Domingo, E., Kanu, N., Dewhurst, S.M., Gronroos, E., et al. (2013). Replication stress links structural and numerical cancer chromosomal instability. Nature 494, 492-496.

McGranahan, N., Burrell, R.A., Endesfelder, D., Novelli, M.R., and Swanton, C. (2012). Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep 13, 528-538.

Tomasetti, C., Li, L., and Vogelstein, B. (2017). Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355, 1330-1334.