Mdm4 supports DNA replication in a p53-independent fashion.
Mdm4 supports DNA replication in a p53-independent fashion.
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DOI：
10.1038/s41388-020-1325-1
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发表时间：
2020-06
期刊：
影响因子：
8
通讯作者：
Dobbelstein M
中科院分区：
文献类型：
--
作者：
Wohlberedt K;Klusmann I;Derevyanko PK;Henningsen K;Choo JAMY;Manzini V;Magerhans A;Giansanti C;Eischen CM;Jochemsen AG;Dobbelstein M
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 analogue 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.
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影响因子：
64.8
作者：
Laurie, Nikia A.;Donovan, Stacy L.;Dyer, Michael A.
通讯作者：
Dyer, Michael A.
影响因子：
7.3
作者：
Li, Yangbing;Yang, Jiuling;Wang, Shaomeng
通讯作者：
Wang, Shaomeng
影响因子：
8.8
作者：
Klusmann, Ina;Rodewald, Sabrina;Dobbelstein, Matthias
通讯作者：
Dobbelstein, Matthias
影响因子：
82.9
作者：
Gembarska, Agnieszka;Luciani, Flavie;Fedele, Clare;Russell, Elisabeth A.;Dewaele, Michael;Villar, Stephanie;Zwolinska, Aleksandra;Haupt, Sue;de Lange, Job;Yip, Dana;Goydos, James;Haigh, Jody J.;Haupt, Ygal;Larue, Lionel;Jochemsen, Aart;Shi, Hubing;Moriceau, Gatien;Lo, Roger S.;Ghanem, Ghanem;Shackleton, Mark;Bernal, Federico;Marine, Jean-Christophe
通讯作者：
Marine, Jean-Christophe
DOI：
10.4161/15384101.2014.949083
发表时间：
2014
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Fischer M;Steiner L;Engeland K
通讯作者：
Engeland K