Page 88 - Read Online

Heinzer et al. J Transl Genet Genom 2024;8:1-12 https://dx.doi.org/10.20517/jtgg.2023.39 Page 5

Figure 1. The cascade of reactions involved in the UPS. (A) The ubiquitination cascade involves the E1, E2, and E3 ubiquitin ligases and
produces a polyubiquitinated end-product. (B) The polyubiquitinated protein is then located by the proteasome which degrades and
deubiquitinates the protein. Created with BioRender.com.

and the RAF-dependent MKK3/p38 signalling pathways, respectively . In humans, HERC1 mutations are
[37]
known to cause a variety of intellectual disability syndromes with or without cerebellar abnormalities .
[38]
Affected individuals are often diagnosed with macrocephaly, motor development delay, and epilepsy, in
addition to intellectual disability .
[39]

RB1CC1
The protein encoded by RB1CC1 (RB1 Inducible Coiled-Coil 1) is a DNA-binding transcription factor (TF),
commonly referred to as FIP200 . It is responsible for activating the expression of the retinoblastoma
[40]
1 (RB1) gene by binding to the GC-rich region found upstream of the promoter . Additionally, it interacts
[41]
with various signalling pathways to regulate cellular processes in a coordinated fashion, including cell-cycle
[42]
progression, differentiation, and senescence, as well as neural migration and neurodegeneration . Overall,
there is strong evidence supporting the role of RB1CC1 as a tumour suppressor as it enhances the
[41]
expression of RB1, a gene in which mutational inactivation can lead to cancer .

SP4
SP4 (Specificity Protein 4 Transcription Factor) encodes a TF which is a member of the Sp/KLF family of
TFs . Similarly to RB1CC1, it recognises GC-rich sequences around the promoters of various genes and
[43]
activates transcription; however, SP4 TFs are restrictively expressed in neuronal cells . Common and rare
[43]
variants in SP4 have been elucidated as risk factors for schizophrenia, possibly through distinct pathological
molecular mechanisms . The SP4 gene has been proposed to play a crucial role in hippocampal
[44]
[45]
development and function and has also been associated with bipolar disorder in humans .

TRIO
TRIO (Trio Rho Guanine Nucleotide Exchange Factor) encodes a guanine nucleotide exchange factor
(GEF), which facilitates the activation of Rho GTPases . The TRIO RhoGEF protein regulates GEF-
[46]