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PMID:20978077

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Citation

Merlet, J, Burger, J, Tavernier, N, Richaudeau, B, Gomes, JE and Pintard, L (2010) The CRL2LRR-1 ubiquitin ligase regulates cell cycle progression during C. elegans development. Development 137:3857-66

Abstract

The molecular mechanisms that regulate cell cycle progression in a developmental context are poorly understood. Here, we show that the leucine-rich repeat protein LRR-1 promotes cell cycle progression during C. elegans development, both in the germ line and in the early embryo. Our results indicate that LRR-1 acts as a nuclear substrate-recognition subunit of a Cullin 2-RING E3 ligase complex (CRL2(LRR-1)), which ensures DNA replication integrity. LRR-1 contains a typical BC/Cul-2 box and binds CRL2 components in vitro and in vivo in a BC/Cul-2 box-dependent manner. Loss of lrr-1 function causes cell cycle arrest in the mitotic region of the germ line, resulting in sterility due to the depletion of germ cells. Inactivation of the DNA replication checkpoint signaling components ATL-1 and CHK-1 suppresses this cell cycle arrest and, remarkably, restores lrr-1 mutant fertility. Likewise, in the early embryo, loss of lrr-1 function induces CHK-1 phosphorylation and a severe cell cycle delay in P lineage division, causing embryonic lethality. Checkpoint activation is not constitutive in lrr-1 mutants but is induced by DNA damage, which may arise due to re-replication of some regions of the genome as evidenced by the accumulation of single-stranded DNA-replication protein A (ssDNA-RPA-1) nuclear foci and the increase in germ cell ploidy in lrr-1 and lrr-1; atl-1 double mutants, respectively. Collectively, these observations highlight a crucial function of the CRL2(LRR-1) complex in genome stability via maintenance of DNA replication integrity during C. elegans development.

Links

PubMed PMC3188596 Online version:10.1242/dev.054866

Keywords

Amino Acid Sequence; Animals; Caenorhabditis elegans/cytology; Caenorhabditis elegans/embryology; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/metabolism; Cell Cycle; Cullin Proteins/metabolism; DNA Replication; Genomic Instability; Molecular Sequence Data; Proteins/metabolism; Ubiquitin-Protein Ligases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:G5ECR7

enables

GO:0019904: protein domain specific binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00018016

F

Seeded From UniProt

complete

CAEEL:CUL2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00018016

F

Seeded From UniProt

complete

CAEEL:Q19988

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00001235
WB:WBGene00001236

F

Seeded From UniProt

complete

CAEEL:Q19988

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00000837

F

Seeded From UniProt

complete

CAEEL:Q19988

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00000516

F

Seeded From UniProt

complete

CAEEL:Q19988

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:Q19988

involved_in

GO:0033314: mitotic DNA replication checkpoint signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00252207

P

Seeded From UniProt

complete

CAEEL:Q19988

involved_in

GO:0033314: mitotic DNA replication checkpoint signaling

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000498

P

Seeded From UniProt

complete

CAEEL:Q19988

involved_in

GO:0033314: mitotic DNA replication checkpoint signaling

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000226

P

Seeded From UniProt

complete

CAEEL:Q19988

part_of

GO:0031462: Cul2-RING ubiquitin ligase complex

ECO:0000305: curator inference used in manual assertion

GO:0005515

C

Seeded From UniProt

complete

CAEEL:Q9BKS1

enables

GO:0019904: protein domain specific binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00018016

F

Seeded From UniProt

complete


See also

References

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