MDM4

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The MCM complex consisting of this protein and MCM2, 6 and 7 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The phosphorylation of this protein by CDC2 kinase reduces the DNA helicase activity and chromatin binding of the MCM complex. This gene is mapped to a region on the chromosome 8 head-to-head next to the PRKDC/DNA-PK, a DNA-activated protein kinase involved in the repair of DNA double-strand breaks. Alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

Full Name

Minichromosome Maintenance Complex Component 4

Function

Along with MDM2, contributes to TP53 regulation (PubMed:32300648).

Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.

Biological Process

Atrial septum development Source: BHF-UCL
Atrioventricular valve morphogenesis Source: BHF-UCL
Cellular response to hypoxia Source: UniProtKB
DNA damage response, signal transduction by p53 class mediator Source: UniProtKB
Endocardial cushion morphogenesis Source: BHF-UCL
Heart valve development Source: BHF-UCL
Negative regulation of apoptotic process Source: InterPro
Negative regulation of cell population proliferation Source: ProtInc
Negative regulation of protein catabolic process Source: UniProtKB
Negative regulation of transcription, DNA-templated Source: ComplexPortal
Negative regulation of transcription by RNA polymerase II Source: UniProtKB
Protein-containing complex assembly Source: UniProtKB
Protein stabilization Source: UniProtKB
Regulation of cell cycle Source: InterPro
Regulation of transcription by RNA polymerase II Source: GO_Central
Ventricular septum development Source: BHF-UCL

Cellular Location

Nucleus

Involvement in disease

Bone marrow failure syndrome 6 (BMFS6):
A form of bone marrow failure syndrome, a heterogeneous group of life-threatening disorders characterized by hematopoietic defects in association with a range of variable extra-hematopoietic manifestations. BMFS6 is an autosomal dominant form characterized by intermittent neutropenia, lymphopenia, or anemia associated with hypocellular bone marrow, and increased susceptibility to cancer.

PTM

Phosphorylated. Phosphorylation at Ser-367 promotes interaction with YWHAG and subsequent ubiquitination and degradation. Phosphorylation at Ser-342 also induces ubiquitination and degradation but to a lower extent.
Ubiquitinated and degraded by MDM2. Deubiquitination by USP2 on the other hand stabilizes the MDM4 protein.