LRWD1 is a 647 amino acid protein that contains five WD domains and three LRR (leucine-rich) repeats. LRWD1 undergoes post-translational phosphorylation, most likely by ATR or ATM, and is encoded by a gene that maps to human chromosome 7. Human chromosome 7 is about 158 milllion bases long, encodes over 1000 genes and makes up about 5% of the human genome. Chromosome 7 has been linked to Osteogenesis imperfecta, Pendred syndrome, Lissencephaly, Citrullinemia and Shwachman-Diamond syndrome. The deletion of a portion of the q arm of chromosome 7 is associated with Williams-Beuren syndrome, a condition characterized by mild mental retardation, an unusual comfort and friendliness with strangers and an elfin appearance.
Function:
Associated component of the origin recognition complex (ORC) required to recruit and stabilize the ORC complex to chromatin. Probably required for the association of ORC on chromatin during G1 to establish pre-replication complex (preRC) and to heterochromatic sites in post-replicated cells. Binds a combination of DNA and histone methylation repressive marks on heterochromatin: binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3 in a cooperative manner with DNA methylation. It is unclear whether it recongnizes and binds these repressive marks by itself or needs additional factors.
Subunit:
Integral component of the ORC complex. Directly interacts with CDT1, GMNN and ORC2. Interacts with ORC2 only when non-ubiquitinated; this interaction prevents LRWD1 ubiquitination and degradation. Some of these interactions are regulated in a cell-cycle dependent manner. Interaction with ORC1 occurs predominantly during G1. Association with phosphorylated ORC1 during mitosis is not efficient. Interaction with CDT1 occurs during G1 phase, as well as during mitosis with phosphorylated CDT1. Interaction with GMNN occurs from G1/S to mitosis. Interaction with ORC2 is observed throughout the cell cycle. The stoichiometry of the ORCA/ORC/CDT1/GMNN complex is 1:1:1:2. Interacts with CUL4A and DDB1; this interaction may lead to ubiquitination.
Subcellular Location:
Nucleus. Chromosome > centromere. Chromosome > telomere. Localizes to heterochromatin during G1 phase. Restricted to centromeres or telomeres as cells progress though S phase. When cells enter mitosis, relocalizes to centromeres.
Tissue Specificity:
Testis-specific. Drastically down-regulated in testis from patients with Sertoli cell-only syndrome (SCOS).
Post-translational modifications:
Phosphorylated upon DNA damage, probably by ATM or ATR.
Similarity:
Belongs to the LRWD1 family.
Contains 3 LRR (leucine-rich) repeats.
Contains 5 WD repeats.
SWISS:
Q9UFC0
Gene ID:
222229
Database links:
Entrez Gene: 222229 Human
SwissProt: Q9UFC0 Human
Unigene: 274135 Human
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