SET

The protein encoded by this gene inhibits acetylation of nucleosomes, especially histone H4, by histone acetylases (HAT). This inhibition is most likely accomplished by masking histone lysines from being acetylated, and the consequence is to silence HAT-dependent transcription. The encoded protein is part of a complex localized to the endoplasmic reticulum but is found in the nucleus and inhibits apoptosis following attack by cytotoxic T lymphocytes. This protein can also enhance DNA replication of the adenovirus genome. Several transcript variants encoding different isoforms have been found for this gene.

Full Name

SET

Function

Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning. Isoform 2 anti-apoptotic activity is mediated by inhibition of the GZMA-activated DNase, NME1. In the course of cytotoxic T-lymphocyte (CTL)-induced apoptosis, GZMA cleaves SET, disrupting its binding to NME1 and releasing NME1 inhibition. Isoform 1 and isoform 2 are potent inhibitors of protein phosphatase 2A. Isoform 1 and isoform 2 inhibit EP300/CREBBP and PCAF-mediated acetylation of histones (HAT) and nucleosomes, most probably by masking the accessibility of lysines of histones to the acetylases. The predominant target for inhibition is histone H4. HAT inhibition leads to silencing of HAT-dependent transcription and prevents active demethylation of DNA. Both isoforms stimulate DNA replication of the adenovirus genome complexed with viral core proteins; however, isoform 2 specific activity is higher.

Biological Process

Biological Process DNA replicationManual Assertion Based On ExperimentTAS:ProtInc
Biological Process negative regulation of DNA-templated transcriptionManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process negative regulation of histone acetylationManual Assertion Based On ExperimentTAS:UniProtKB
Biological Process negative regulation of neuron apoptotic processManual Assertion Based On ExperimentIGI:MGI
Biological Process nucleosome assemblyManual Assertion Based On ExperimentTAS:ProtInc
Biological Process nucleosome disassemblyManual Assertion Based On ExperimentTAS:UniProtKB

Cellular Location

Cytoplasm, cytosol
Endoplasmic reticulum
Nucleus, nucleoplasm
In the cytoplasm, found both in the cytosol and associated with the endoplasmic reticulum. The SET complex is associated with the endoplasmic reticulum. Following CTL attack and cleavage by GZMA, moves rapidly to the nucleus, where it is found in the nucleoplasm, avoiding the nucleolus. Similar translocation to the nucleus is also observed for lymphocyte-activated killer cells after the addition of calcium.

Involvement in disease

Intellectual developmental disorder, autosomal dominant 58 (MRD58):
A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD58 patients show delayed development, intellectual disability, language delay and speech impairment. Some patients have motor delay or incoordination, and minor dysmorphic features.

PTM

Isoform 2 is phosphorylated on Ser-15 and Ser-24.
Isoform 2 is acetylated on Lys-11.
Some glutamate residues are glycylated by TTLL8. This modification occurs exclusively on glutamate residues and results in a glycine chain on the gamma-carboxyl group (By similarity).
N-terminus of isoform 1 is methylated by METTL11A/NTM1. Mainly trimethylated (By similarity).
Isoform 2
Cleaved after Lys-176 by GZMA. The cleavage inhibits its nucleosome assembly activity and disrupts the inhibition on NME1.