| Elongator complex protein 3 (Elp3/KAT9) is the catalytic acetyltransferase subunit of the six‑component Elongator complex and functions at the intersection of chromatin regulation, tRNA modification and stress-responsive genome maintenance. The protein contains a GNAT‑family acetyltransferase domain and forms part of an intact Elongator assembly together with other subunits that is required for its activities; mutations in Elp3 or other Elongator components that compromise complex formation lead to comparable phenotypes, indicating that Elp3 acts within a multi-subunit unit rather than as an isolated enzyme. As a histone acetyltransferase associated with RNA polymerase II, Elp3 acetylates histones H3 and likely H4 and contributes to transcriptional elongation, transcriptional silencing and chromatin remodeling, and in yeast Elongator interacts directly with proliferating cell nuclear antigen (PCNA), linking acetylation and elongation functions to DNA replication– and repair–coupled nucleosome assembly. Cells lacking Elp3 display partial loss of silencing of reporter genes at telomeric and silent mating-type loci, increased sensitivity to the DNA replication inhibitor hydroxyurea and the damaging agent methyl methanesulfonate, and defects in S-phase progression under replication stress, situating Elp3 in pathways that maintain genome stability during transcription and DNA synthesis. Epistasis analyses show that elp3 deletion exacerbates the sensitivity of mutants lacking histone chaperones Asf1 or CAF‑1 or the H3K56 acetyltransferase Rtt109, and allele-specific genetic interactions with POL30 (PCNA) together with in vivo and in vitro binding of PCNA to Elongator indicate that Elp3 functions in a PCNA-linked pathway that couples chromatin assembly, transcriptional silencing and replication stress responses. Beyond chromatin, Elp3 is implicated in post-transcriptional tRNA modification across eukaryotes, and Elongator has been associated with α‑tubulin acetylation and neuronal migration, placing Elp3 in a broader family context of acetyltransferases that act on histones, tubulin and RNA-related substrates to coordinate transcription and translation with cytoskeletal dynamics. In tumor biology, Elp3 is induced by Wnt signaling and is required for colon cancer initiation and regeneration through regulation of Sox9 translation; Elp3 affects tRNA modification that supports efficient translation of Sox9, and genetic or experimental reduction of Elp3 activity impairs Wnt‑dependent tumor initiation and regenerative capacity in intestinal epithelium. Elp3 also stabilizes the oncogenic transcription factor c‑Myc in colorectal and hepatocellular carcinoma by binding c‑Myc and competing with the E3 ligase FBXW7β, thereby reducing FBXW7β-mediated ubiquitination and proteasomal degradation of c‑Myc, and Elp3 knockdown diminishes glycolysis, glutaminolysis, cell proliferation and xenograft growth, effects that can be rescued by c‑Myc reconstitution. |
