RBX1 (RING box protein 1) E3 ubiquitin ligase is required for genomic integrity by modulating DNA replication licensing proteins.
RBX1 (RING box protein 1), also known as ROC1 (Regulator of Cullin 1), is an essential component of SCF (Skp1/Cullins/F-box) E3 ubiquitin ligases, which target diverse proteins for proteasome-mediated degradation. Our recent study showed that RBX1 silencing triggered a DNA damage response (DDR) leading to G(2)-M arrest, senescence, and apoptosis, with the mechanism remaining elusive. Here, we show that, in human cancer cells, RBX1 silencing causes the accumulation of DNA replication licensing proteins CDT1 and ORC1, leading to DNA double-strand breaks, DDR, G(2) arrest, and, eventually, aneuploidy. Whereas CHK1 activation by RBX1 silencing is responsible for the G(2) arrest, enhanced DNA damage renders cancer cells more sensitive to radiation. In Caenorhabditis elegans, RBX-1 silencing causes CDT-1 accumulation, triggering DDR in intestinal cells, which is largely abrogated by simultaneous CDT-1 silencing. RBX-1 silencing also induces lethality during development of embryos and in adulthood. Thus, RBX1 E3 ligase is essential for the maintenance of mammalian genome integrity and the proper development and viability in C. elegans.
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA. jialijun2002@yahoo.com.cn
Lijun
L
Jia
Jeremy S
JS
Bickel
Jiaxue
J
Wu
Meredith A
MA
Morgan
Hua
H
Li
Jie
J
Yang
Xiaochun
X
Yu
Raymond C
RC
Chan
Yi
Y
Sun
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004261:DNA Replication; D004625:Embryo, Nonmammalian; D020868:Gene Silencing; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D051738:Origin Recognition Complex / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
C467199:CDT1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D051738:Origin Recognition Complex; C479529:RBX1 protein, human; D044767:Ubiquitin-Protein Ligases