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|Public on Jul 01, 2023
|GNL3/nucleostemin links DNA replication homeostasis and replication forks stability
|Genome variation profiling by array
|The regulation of replication forks stalling and replication origins firing must be tightly coordinated to prevents genomic instability. Here we show that GNL3/nucleostemin, a GTP-binding protein able to shuttle between the nucleolus and the nucleoplasm, limits replicative stress by limiting replication origins firing. GNL3 is in proximity of nascent DNA and its depletion reduces forks speed but increases forks density and replication origins firing. When subjected to exogenous replicative stress, cells impaired for GNL3 exhibits MRN-dependent resection and RPA phosphorylation. Strikingly, inhibition of origin firing using CDC7 inhibitor decreased resection in absence of GNL3 but not in absence of BRCA1, suggesting that GNL3 does not protect nascent strand directly from resection. Consistent with this, overexpression of GNL3 leads to an increased resection in response to replicative stress and enhanced origin firing efficiency. These data indicate that the probability of origins firing is tightly regulated by GNL3 to limit replicative stress. Finally, we show that ORC2 and GNL3 interacts together in the nucleolus. We propose a model where GNL3 level is crucial to determine the correct amount of ORC2 on chromatin by sequestrating it in the nucleolus thanks to the capacity of GNL3 to shuttle between nucleoplasm and nucleolus.
|nascent-DNA from early S-phase versus nascent-DNA from late S-phase
|Lebdy R, Canut M, Patouillard J, Cadoret J, Letessier A, Basbous J, Miotto B, Constantinou A, Abou-Merhi R, Ribeyre C
|Jul 26, 2021
|Last update date
|Jul 03, 2023
|CNRS/ Université de Paris
|15 rue hélène Brion
|Agilent-022060 SurePrint G3 Human CGH Microarray 4x180K (Feature Number version)
|TAR (of TXT)