{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTWNK encodes the mitochondrial replicative helicase “Twinkle,” a protein central to mtDNA metabolism. Biochemical and structural studies have revealed that Twinkle self‐assembles into stable hexameric rings that bind both single‐ and double‐stranded DNA. It unwinds duplex DNA in a 5′–3′ direction during mtDNA replication and also displays unique strand–annealing, strand–exchange, and branch–migration activities that may facilitate recombination–mediated replication restart and repair. Notably, its N–terminal region—which, despite showing motifs reminiscent of phage T7 primase, lacks primase activity—is required for efficient single–stranded DNA binding, supporting proper replisome processivity. These findings, together with high–resolution imaging and solution studies of its conformational dynamics, underscore Twinkle’s critical role as a motor protein in mitochondrial genome maintenance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its core helicase activity, Twinkle is a pivotal component of the mitochondrial replisome that organizes mtDNA into discrete, protein–rich nucleoids. Cellular and biochemical investigations demonstrate that Twinkle colocalizes with factors such as TFAM and mtSSB, further implicating it in the regulation of mtDNA transcription and replication fork progression. Expression of dominant–negative mutations leads to replication pausing or stalling, favoring the accumulation of replication intermediates—and, in certain contexts, the formation of multiple mtDNA deletions or depletion. Moreover, Twinkle’s incompetent unwinding of specific DNA structures, such as G–quadruplexes, may represent an additional source of mitochondrial genome instability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in TWNK give rise to a spectrum of human mitochondrial disorders. Autosomal dominant variants are most notably associated with progressive external ophthalmoplegia (PEO), characterized by muscle weakness and multiple mtDNA deletions, while recessive mutations can result in infantile–onset spinocerebellar ataxia (IOSCA), hepatocerebral syndromes, and even Perrault syndrome—with features ranging from early encephalopathy and liver dysfunction to sensorineural hearing loss and gonadal dysgenesis. Clinical investigations—in families from diverse geographical origins and through various genetic approaches—have underscored the importance of proper Twinkle oligomerization, nucleotide hydrolysis, and strand–separation in maintaining mitochondrial function, with even subtle changes causing pronounced neuromuscular and multisystemic disease phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tawn D Ziebarth, Carol L Farr, Laurie S Kaguni "}, {"type": "b", "children": [{"type": "t", "text": "Modular architecture of the hexameric human mitochondrial DNA helicase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2007.01.079"}], "href": "https://doi.org/10.1016/j.jmb.2007.01.079"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17324440"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17324440"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Robert H Baloh, Ezequiel Salavaggione, Jeffrey Milbrandt, et al. 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