Open AccessMdm4 supports DNA replication in a p53-independent fashion
Author(s) -
Kai Wohlberedt,
Kazuo Ina,
Polina K. Derevyanko,
Kester Mo Henningsen,
Josephine Ann Mun Yee Choo,
Valentina Manzini,
Anna Magerhans,
Celeste Giansanti,
Christine M. Eischen,
Aart G. Jochemsen,
Matthias Dobbelstein
Publication year - 2020
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/s41388-020-1325-1
Subject(s) - biology , control of chromosome duplication , dna replication , replication factor c , dna replication factor cdt1 , dna damage , minichromosome maintenance , eukaryotic dna replication , dna re replication , microbiology and biotechnology , origin recognition complex , mdmx , pre replication complex , mdm2 , dna , genetics , gene
The Mdm4 (alias MdmX) oncoprotein, like its paralogue and interaction partner Mdm2, antagonizes the tumor suppressor p53. p53-independent roles of the Mdm proteins are emerging, and we have reported the ability of Mdm2 to modify chromatin and to support DNA replication by suppressing the formation of R-loops (DNA/RNA-hybrids). We show here that the depletion of Mdm4 in p53-deficient cells compromises DNA replication fork progression as well. Among various deletion mutants, only full-length Mdm4 was able to support DNA replication fork progression. Co-depletion of Mdm4 and Mdm2 further impaired DNA replication, and the overexpression of each partially compensated for the other's loss. Despite impairing replication, Mdm4 depletion only marginally hindered cell proliferation, likely due to compensation through increased firing of replication origins. However, depleting Mdm4 sensitized p53-/- cells to the nucleoside analog gemcitabine, raising the future perspective of using Mdm4 inhibitors as chemosensitizers. Mechanistically, Mdm4 interacts with members of the Polycomb Repressor Complexes and supports the ubiquitination of H2A, thereby preventing the accumulation of DNA/RNA-hybrids. Thus, in analogy to previously reported activities of Mdm2, Mdm4 enables unperturbed DNA replication through the avoidance of R-loops.