Tripartite Motif Containing 24, or TRIM24, is a protein involved in fundamental biological processes. It acts as a regulator, influencing how cells grow, divide, and respond to their environment. Understanding TRIM24 provides insights into the cellular machinery and how its disruptions can lead to various health issues.
The Architecture of TRIM24
TRIM24 has a distinctive structure with several specialized domains. At its N-terminal end, TRIM24 features a TRIM motif, common to the Tripartite Motif (TRIM) family. This motif includes a RING domain, followed by one or two B-box zinc fingers, and a coiled-coil region.
The RING domain, a zinc finger, is involved in protein-protein interactions and facilitates ubiquitination. Following the B-box domains, the coiled-coil region forms a helical structure that promotes the assembly of TRIM24 into larger complexes with other proteins. Towards its C-terminus, TRIM24 includes a Plant Homeodomain (PHD) and a bromodomain, often found together. These domains “read” specific modifications on histone proteins, which package DNA in the cell nucleus. The PHD-bromodomain region specifically recognizes unmodified histone H3 at lysine 4 (H3K4me0) and acetylated histone H3 at lysine 23 (H3K23ac).
TRIM24’s Diverse Functions
TRIM24 acts as an E3-ubiquitin ligase, an enzyme that attaches ubiquitin tags to proteins. This ubiquitination can mark proteins for degradation, controlling their levels within the cell. For instance, TRIM24 promotes the ubiquitination and subsequent degradation of the tumor suppressor protein p53, thereby influencing cell proliferation and programmed cell death.
Beyond protein degradation, TRIM24 is also involved in transcriptional control, regulating gene activity. It functions as a transcriptional coactivator, interacting with various nuclear receptors and coactivators to modulate the expression of target genes. This includes up-regulating ligand-dependent transcription activated by androgen, glucocorticoid, thyroid hormone, and estrogen receptors. It also regulates transcription activated by retinoic acid receptors, such as RARA, influencing processes like retinoic acid-dependent proliferation in liver cells.
TRIM24’s interaction with chromatin (DNA and proteins forming chromosomes) is influenced by histone H3 modifications. Its PHD and bromodomain regions specifically recognize certain histone marks, allowing it to influence gene expression by interpreting these modifications. This connection to chromatin and nuclear receptors highlights its broad impact on how genes are turned on or off in the cell.
TRIM24 also contributes to the DNA damage response, a system that detects and repairs DNA damage. In response to DNA damage, the ATM kinase phosphorylates TRIM24, leading to its recruitment to sites of DNA double-strand breaks. This recruitment facilitates the accumulation of the MRN complex, a group of proteins involved in DNA repair. Furthermore, DNA damage-activated p53 can directly induce the transcription of TRIM24, creating a feedback loop where newly synthesized TRIM24 then targets phosphorylated p53 for degradation, helping to terminate the DNA damage response.
TRIM24’s Link to Health and Disease
Aberrant activity of TRIM24 is linked to the development and progression of various human cancers. Overexpression of TRIM24 is observed in several cancer types, including breast, prostate, lung, and liver cancers, and is associated with a less favorable prognosis. In breast cancer, for example, high levels of TRIM24 negatively correlate with patient survival.
In prostate cancer, TRIM24 can promote cell proliferation, particularly under low androgen conditions, and it enhances androgen receptor signaling. Genes co-activated by androgen receptor and TRIM24 are notably upregulated in castration-resistant prostate cancer, a more aggressive form of the disease. Similarly, in non-small cell lung cancer, increased TRIM24 expression correlates with advanced tumor stages and poorer differentiation.
TRIM24’s role in hepatocellular carcinoma (liver cancer) is complex; while some studies suggest it can suppress tumor development in mice, its overexpression in human tissues is associated with higher rates of intrahepatic metastasis, recurrence, and shorter tumor-free survival. Its ability to ubiquitinate and degrade p53, a tumor suppressor, further contributes to its oncogenic potential when dysregulated.
Given its involvement in cancer progression, TRIM24 is being explored as a potential target for therapeutic interventions. Studies have investigated specific TRIM24 inhibitors, such as dTRIM24 and IACS-9571, to suppress cancer cell growth and invasion. These inhibitors have shown promise in inhibiting the propagation and invasion of glioblastoma stem cells, partly by disrupting the TRIM24-SOX2 axis, which promotes cancer stemness. The development of compounds that can specifically target TRIM24’s domains, like its PHD and bromodomain, is an ongoing area of research, aiming to create new treatments for various cancers.