InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: DTL

Summary

InnateDB Protein

IDBP-106537.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

DTL

Protein Name

denticleless homolog (Drosophila)

Synonyms

Species

Homo sapiens

Ensembl Protein

ENSP00000355958

InnateDB Gene

IDBG-106535 (DTL)

Protein Structure

UniProt Annotation

Function

Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis. The DCX(DTL) complex, also named CRL4(CDT2) complex, mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1) and SETD8. CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication. CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing. SETD8 degradation is also important for a proper regulation of mechanisms such as TGF-beta signaling, cell cycle progression, DNA repair and cell migration. Most substrates require their interaction with PCNA for their polyubiquitination: substrates interact with PCNA via their PIP-box, and those containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to their degradation. In undamaged proliferating cells, the DCX(DTL) complex also promotes the 'Lys-164' monoubiquitination of PCNA, thereby being involved in PCNA- dependent translesion DNA synthesis. {ECO:0000269PubMed:16861906, ECO:0000269PubMed:16949367, ECO:0000269PubMed:16964240, ECO:0000269PubMed:17085480, ECO:0000269PubMed:18703516, ECO:0000269PubMed:18794347, ECO:0000269PubMed:18794348, ECO:0000269PubMed:19332548, ECO:0000269PubMed:20129063, ECO:0000269PubMed:23478441, ECO:0000269PubMed:23478445}.

Subcellular Localization

Nucleus. Nucleus membrane; Peripheral membrane protein; Nucleoplasmic side. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Chromosome. Note=Nuclear matrix-associated protein. Translocates from the interphase nucleus to the metaphase cytoplasm during mitosis.

Disease Associations

Tissue Specificity

Expressed in placenta and testis, very low expression seen in skeletal muscle. Detected in all hematopoietic tissues examined, with highest expression in thymus and bone marrow. A low level detected in the spleen and lymph node, and barely detectable level in the peripheral leukocytes. RA treatment down-regulated the expression in NT2 cell. {ECO:0000269PubMed:11278750, ECO:0000269PubMed:17106265}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 55 experimentally validated interaction(s) in this database.

Experimentally validated
Total	55 [view]
Protein-Protein	53 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004842	ubiquitin-protein transferase activity
GO:0005515	protein binding

Biological Process

GO:0000209	protein polyubiquitination
GO:0006260	DNA replication
GO:0006511	ubiquitin-dependent protein catabolic process
GO:0006513	protein monoubiquitination
GO:0006974	cellular response to DNA damage stimulus
GO:0009411	response to UV
GO:0019985	translesion synthesis
GO:0031572	G2 DNA damage checkpoint
GO:0051726	regulation of cell cycle

Cellular Component

GO:0005634	nucleus
GO:0005694	chromosome
GO:0005730	nucleolus
GO:0005737	cytoplasm
GO:0005813	centrosome
GO:0031464	Cul4A-RING E3 ubiquitin ligase complex
GO:0031465	Cul4B-RING E3 ubiquitin ligase complex
GO:0031965	nuclear membrane
GO:0043231	intracellular membrane-bounded organelle