| TDRD3 is a multidomain Tudor family protein that functions as a reader of asymmetric dimethyl‑arginine marks and links arginine methylation to transcriptional control, R‑loop metabolism, and RNA stress–response compartments. The protein contains an N‑terminal ubiquitin‑associated domain, a central Tudor domain with a defined methyl‑arginine–binding surface, and additional low‑complexity and nucleic acid–recognition regions that support scaffolding of protein and RNA complexes. The Tudor domain recognizes asymmetric dimethyl‑arginine on histone H3 Arg17 and histone H4 Arg3, marks written mainly by PRMT1 and associated with transcriptional activation, and this binding recruits TDRD3 to active chromatin at promoters and enhancers where arginine‑methylated tails are present. At these loci, TDRD3 acts as a coactivator by bringing in additional factors such as Topoisomerase IIIβ and helicases including DHX9, which relax negatively supercoiled DNA and resolve R‑loops that arise during high transcriptional output, thereby supporting continued elongation and limiting exposure of persistent DNA–RNA hybrids. Direct interaction between the TDRD3 Tudor domain and DHX9 guides DHX9 to specific promoters, and loss of TDRD3 reduces DHX9 chromatin occupancy and increases promoter‑proximal R‑loop accumulation, illustrating a defined pathway in which methyl‑histone reading and helicase recruitment converge on genome stability maintenance at transcribed genes. TDRD3 also localizes to translating polyribosomes and accumulates in cytoplasmic stress granules upon diverse stress stimuli; in these structures, it binds dimethyl‑arginine–containing RNA‑binding proteins, including G3BP1, via its Tudor domain and promotes stress granule assembly by enhancing RNA binding and increasing the valence of protein–RNA interaction networks that drive liquid–liquid phase separation. PRMT1 methylates key stress granule RBPs on RGG motifs, and TDRD3 acts as the methyl‑mark reader in this writer–reader pair, so coordinated PRMT1–TDRD3 activity regulates the threshold and dynamics of stress granule formation and influences how translationally stalled mRNAs are partitioned during stress. |
