The oncoprotein DEK affects the outcome of PARP1/2 inhibition during mild replication stress.
Bone Neoplasms
/ drug therapy
Chromosomal Proteins, Non-Histone
/ genetics
DNA Damage
DNA Replication
Genomic Instability
Humans
Oncogene Proteins
/ genetics
Osteosarcoma
/ drug therapy
Poly (ADP-Ribose) Polymerase-1
/ antagonists & inhibitors
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Poly(ADP-ribose) Polymerases
/ chemistry
Poly-ADP-Ribose Binding Proteins
/ genetics
Tumor Cells, Cultured
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
15
02
2019
accepted:
03
07
2019
entrez:
14
8
2019
pubmed:
14
8
2019
medline:
4
3
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31408463
doi: 10.1371/journal.pone.0213130
pii: PONE-D-19-04568
pmc: PMC6692024
doi:
Substances chimiques
Chromosomal Proteins, Non-Histone
0
DEK protein, human
0
Oncogene Proteins
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Poly-ADP-Ribose Binding Proteins
0
PARP1 protein, human
EC 2.4.2.30
PARP2 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0213130Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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