The oncoprotein DEK affects the outcome of PARP1/2 inhibition during mild replication stress.
Magdalena GanzChristopher VogelChristina CzadaVera JörkeEva Christina GwoschRebecca KleinerAgnieszka Pierzynska-MachFrancesca Cella ZanacchiAlberto DiasproFerdinand KappesAlexander BürkleElisa Ferrando-MayPublished in: PloS one (2019)
DNA replication stress is a major source of genomic instability and is closely linked to tumor formation and progression. Poly(ADP-ribose)polymerases1/2 (PARP1/2) enzymes are activated in response to replication stress resulting in poly(ADP-ribose) (PAR) synthesis. PARylation plays an important role in the remodelling and repair of impaired replication forks, providing a rationale for targeting highly replicative cancer cells with PARP1/2 inhibitors. The human oncoprotein DEK is a unique, non-histone chromatin architectural protein whose deregulated expression is associated with the development of a wide variety of human cancers. Recently, we showed that DEK is a high-affinity target of PARylation and that it promotes the progression of impaired replication forks. Here, we investigated a potential functional link between PAR and DEK in the context of replication stress. Under conditions of mild replication stress induced either by topoisomerase1 inhibition with camptothecin or nucleotide depletion by hydroxyurea, we found that the effect of acute PARP1/2 inhibition on replication fork progression is dependent on DEK expression. Reducing DEK protein levels also overcomes the restart impairment of stalled forks provoked by blocking PARylation. Non-covalent DEK-PAR interaction via the central PAR-binding domain of DEK is crucial for counteracting PARP1/2 inhibition as shown for the formation of RPA positive foci in hydroxyurea treated cells. Finally, we show by iPOND and super resolved microscopy that DEK is not directly associated with the replisome since it binds to DNA at the stage of chromatin formation. Our report sheds new light on the still enigmatic molecular functions of DEK and suggests that DEK expression levels may influence the sensitivity of cancer cells to PARP1/2 inhibitors.
Keyphrases
- dna damage
- stress induced
- dna repair
- poor prognosis
- endothelial cells
- binding protein
- gene expression
- clinical trial
- oxidative stress
- single molecule
- high resolution
- intensive care unit
- mass spectrometry
- hepatitis b virus
- cancer therapy
- liver failure
- cell free
- optical coherence tomography
- extracorporeal membrane oxygenation
- acute respiratory distress syndrome
- sickle cell disease
- circulating tumor cells
- drug induced