The oncoprotein DEK affects the outcome of PARP1/2 inhibition during mild replication stress.

Ganz, Magdalena

Vogel, Christopher

Czada, Christina

Jörke, Vera

Gwosch, Eva Christina

Kleiner, Rebecca

Pierzynska-Mach, Agnieszka

Zanacchi, Francesca Cella

Diaspro, Alberto

Kappes, Ferdinand

Bürkle, Alexander

Ferrando-May, Elisa

2022-07-28T05:47:44Z

2022-07-28T05:47:44Z

2019-01

2022-07-28T05:47:16Z

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.

PONE-D-19-04568

1932-6203

1932-6203

https://hdl.handle.net/10161/25519

eng

Public Library of Science (PLoS)

PloS one

10.1371/journal.pone.0213130

Tumor Cells, Cultured

Humans

Osteosarcoma

Bone Neoplasms

DNA Damage

Genomic Instability

Poly(ADP-ribose) Polymerases

Oncogene Proteins

Chromosomal Proteins, Non-Histone

DNA Replication

Poly(ADP-ribose) Polymerase Inhibitors

Poly (ADP-Ribose) Polymerase-1

Poly-ADP-Ribose Binding Proteins

The oncoprotein DEK affects the outcome of PARP1/2 inhibition during mild replication stress.

Journal article

Kappes, Ferdinand|0000-0002-0369-0065

e0213130

8

Duke

Duke Kunshan University

DKU Faculty

Published

14