SAMHD1 promotes oncogene-induced replication stress

Abstract

Oncogenes induce DNA replication stress in cancer cells. Although this was established more than a decade ago, we are still unravelling the molecular underpinnings of this phenomenon, which will be critical if we are to exploit this knowledge to improve cancer treatment. A key mediator of oncogene-induced replication stress is the availability of DNA precursors, which will limit ongoing DNA synthesis by cellular replicases. In this study, we identify a potential role for nucleotide catabolism in promoting replication stress induced by oncogenes. Specifically, we establish that the dNTPase SAMHD1 slows DNA replication fork speeds in human fibroblasts harbouring an oncogenic RAS allele, elevating levels of endogenous DNA damage, and ultimately limiting cell proliferation. We then show that oncogenic RAS-driven tumours express reduced SAMHD1 levels, suggesting they have overcome this tumour suppressor barrier, and that this correlates with worse overall survival for these patients.Abstract Figure

Targeting the DNA damage response and repair in cancer through nucleotide metabolism

“…Cell cycle arrest was attributed to perturbed assembly of preinitiation complexes at replication origins; whether this is the case in human cells with expanded dNTP pools remains to be investigated. Perhaps critically, these differential impacts of SAMHD1 upon cancer biology would be impacted by the cellular context, depending upon which oncogene is driving cancer cell proliferation [ 139 ], the metabolic wiring of the cell, and competency of genome stability pathways, for instance. Many open questions remain to be investigated here.…”