The SCFFSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans

Gao, Min; Liao, Edward H.; Yu, Bin; Wang, Y; Zhen, Mei; Derry, W. Brent

doi:10.1038/cdd.2008.30

Cited by 43 publications

(36 citation statements)

References 42 publications

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“…S4, A and B). Although the germ line of the rbx-1 RNAi worms had twice as many apoptotic corpses compared with the vector control, an observation consistent with a recent study (41), the cellular defect did not correlate with egl-1 transactivation (data not shown), which is normally required for apoptosis associated with DDR in the germ line (42,43). This finding suggests that the apoptotic response may not be related to DDR.…”

Section: Rbx-1 Silencing Induces Ddr and Lethal Phenotypes In C Elegsupporting

confidence: 79%

RBX1 (RING Box Protein 1) E3 Ubiquitin Ligase Is Required for Genomic Integrity by Modulating DNA Replication Licensing Proteins

Jia

Bickel

et al. 2011

Journal of Biological Chemistry

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RBX1 (RING box protein 1), also known as ROC1 (Regulator of Cullin 1), is an essential component of SCF (Skp1/Cullins/Fbox) 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. SCF (Skp1/Cullins/F-box; also known as CRL (Cullin-RING Ligase) E3 ubiquitin ligases are the largest multiunit E3 ligases that promote the degradation of numerous short-lived cellular proteins, including cell cycle regulators, transcription factors, signal transducers, and oncogene/tumor suppressors (1, 2). A recent global protein stability profiling analysis identified ϳ350 potential SCF substrates, the majority of which were previously unidentified (3). Most recently, a study of SCF inactivation by a small molecule inhibitor of cullin neddylation suggested that up to 20% of ubiquitinated cellular proteins are mediated by SCF E3 for proteasome degradation (4). Thus, SCF E3 ubiquitin ligases regulate many aspects of cellular functions and biological processes under physiological conditions. Dysfunction of SCF is involved in the pathogenesis of a variety of diseases, including cancer (2, 5).The core of SCF ubiquitin ligases is a complex of RBX1-cullins (6). RBX1 consists of 108 amino acids with a C-terminal RING-H2 finger domain required for zinc ion binding and ligase activity (7-9). Crystal structure studies revealed that RBX1 complexes with cullin/F-box proteins form functional SCF E3 ligases that transfer ubiquitin from E2 to specific substrates for proteasome-targeted degradation (10). Previous studies have shown that RBX1 interacts with all seven cullin family members to activate E3 ubiquitin ligases and regulate numerous biological processes by promoting timely degradation of cellular substrates (9, 11).As an essential component of SCF E3 ligase, RBX1 plays a critical role in development. In yeast, deletion of Hrt1, the yeast homolog of RBX1, causes lethality, which can be rescued by human RBX1 or RBX2/SAG (Sensitive to Apoptosis gene) (9,12,13). In Caenorhabditis elegans, RBX-1 is crucial for cell cycle progression and chromosome metabolism, and RBX-1 silencing results in embryonic d...

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Section: Rbx-1 Silencing Induces Ddr and Lethal Phenotypes In C Elegsupporting

confidence: 79%

RBX1 (RING Box Protein 1) E3 Ubiquitin Ligase Is Required for Genomic Integrity by Modulating DNA Replication Licensing Proteins

Jia

Bickel

et al. 2011

Journal of Biological Chemistry

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“…Interestingly, CEP-1 seems to be required for both UV-induced cell cycle arrest and apoptosis (Derry et al 2007 ;Stergiou et al 2007 ) . Like mammalian p53, CEP-1 is phosphorylated in response to ionizing irradiation but the importance of this has not been identi fi ed (Schumacher et al 2005b ;Gao et al 2008 ) . The identi fi cation of CEP-1 and the tremendous interest in the mammalian p53 family prompted searches for CEP-1 regulatory mechanisms.…”

Section: Pathways Leading To Dna Damage-induced Apoptosismentioning

confidence: 99%

“…Skp1/cullin/F-box (SCF) ubiquitin ligases are activated by neddylation of the cullin subunit. The cullin 3 SCF FSN-1 complex is required to dampen the apoptosis response, and likely acts in the same pathway as neddylation (Gao et al 2008 ) . In addition, the level of CEP-1 is signi fi cantly increased in fsn-1 mutants, suggesting that the E3 ubiquitin ligase complex SCF FSN-1 negatively regulates CEP-1 activity in C. elegans germline, possibly by the degradation of CEP-1 (Fig.…”

Section: Cep-1 Regulationmentioning

confidence: 99%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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In the past 12 years, since the fi rst description of C. elegans germ cell apoptosis, this area of research rapidly expanded. It became evident that multiple genetic pathways lead to the apoptotic demise of germ cells. We are only beginning to understand how these pathways that all require the CED-9/Bcl-2, Apaf-1/CED-4 and CED-3 caspase core apoptosis components are regulated. Physiological apoptosis, which likely accounts for the elimination of more than 50% of all germ cells, even in unperturbed conditions, is likely to be required to maintain tissue homeostasis. The best-studied pathways lead to DNA damage-induced germ cell apoptosis in response to a variety of genotoxic stimuli. This apoptosis appears to be regulated similar to DNA damage-induced apoptosis in the mouse germ line and converges on p53 family transcription factors. DNA damage response pathways not only lead to apoptosis induction, but also directly affect DNA repair, and a transient cell cycle arrest of mitotic germ cells. Finally, distinct pathways activate germ cell apoptosis in response to defects in meiotic recombination and meiotic chromosome pairing.

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“…A proof of principle is set by FBXO45, the mammalian ortholog of C. elegans FSN1, an F-box protein that is involved in germ-line apoptosis by regulating the p53-like protein Cep-1. 61 In mammalian cells, FBXO45 binds specifically to p73 and promotes its degradation by an SCF-dependent mechanism. 62 WWP1.…”

Section: Mdm2mentioning

confidence: 99%

p53-family proteins and their regulators: hubs and spokes in tumor suppression

2010

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The tumor suppressor p53 is a central hub in a molecular network controlling cell proliferation and death in response to potentially oncogenic conditions, and a wide array of covalent modifications and protein interactions modulate the nuclear and cytoplasmic activities of p53. The p53 relatives, p73 and p63, are entangled in the same regulatory network, being subject at least in part to the same modifications and interactions that convey signals on p53, and actively contributing to the resulting cellular output. The emerging picture is that of an interconnected pathway, in which all p53-family proteins are involved in the response to oncogenic stress and physiological inputs. Therefore, common and specific interactors of p53-family proteins can have a wide effect on function and dysfunction of this pathway. Many years of research have uncovered an impressive number of p53-interacting proteins, but much less is known about protein interactions of p63 and p73. Yet, many interactors may be shared by multiple p53-family proteins, with similar or different effects. In this study we review shared interactors of p53-family proteins with the aim to encourage research into this field; this knowledge promises to unveil regulatory elements that could be targeted by a new generation of molecules, and allow more efficient use of currently available drugs for cancer treatment.

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The SCFFSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans

Cited by 43 publications

References 42 publications

RBX1 (RING Box Protein 1) E3 Ubiquitin Ligase Is Required for Genomic Integrity by Modulating DNA Replication Licensing Proteins

RBX1 (RING Box Protein 1) E3 Ubiquitin Ligase Is Required for Genomic Integrity by Modulating DNA Replication Licensing Proteins

Germ Cell Apoptosis and DNA Damage Responses

p53-family proteins and their regulators: hubs and spokes in tumor suppression

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