RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage-induced cell senescence.
Mol Biol Cell
; 27(8): 1346-57, 2016 Apr 15.
Article
in En
| MEDLINE
| ID: mdl-26864624
ABSTRACT
The coordination of cell cycle progression with the repair of DNA damage supports the genomic integrity of dividing cells. The function of many factors involved in DNA damage response (DDR) and the cell cycle depends on their Ran GTPase-regulated nuclear-cytoplasmic transport (NCT). The loading of Ran with GTP, which is mediated by RCC1, the guanine nucleotide exchange factor for Ran, is critical for NCT activity. However, the role of RCC1 or Ranâ
GTP in promoting cell proliferation or DDR is not clear. We show that RCC1 overexpression in normal cells increased cellular Ranâ
GTP levels and accelerated the cell cycle and DNA damage repair. As a result, normal cells overexpressing RCC1 evaded DNA damage-induced cell cycle arrest and senescence, mimicking colorectal carcinoma cells with high endogenous RCC1 levels. The RCC1-induced inhibition of senescence required Ran and exportin 1 and involved the activation of importin ß-dependent nuclear import of 53BP1, a large NCT cargo. Our results indicate that changes in the activity of the Ranâ
GTP-regulated NCT modulate the rate of the cell cycle and the efficiency of DNA repair. Through the essential role of RCC1 in regulation of cellular Ranâ
GTP levels and NCT, RCC1 expression enables the proliferation of cells that sustain DNA damage.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Nuclear Proteins
/
Cell Cycle
/
Cell Cycle Proteins
/
Ran GTP-Binding Protein
/
Guanine Nucleotide Exchange Factors
/
DNA Repair
Limits:
Humans
Language:
En
Journal:
Mol Biol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2016
Document type:
Article