Dyskerin dysfunction in cancer development: from telomere dysregulation to immune deficiency

Dyskerin, encoded by the dyskerin pseudouridine synthase 1 (DKC1) gene, is a core component of the H/ACA ribonucleoprotein complex and plays essential roles in telomerase activity maintenance, rRNA pseudouridylation, and ribosome biogenesis. Loss of DKC1 function represents a major pathogenic basis of dyskeratosis congenita (DC) and is associated with a markedly increased risk of malignancy, particularly head and neck squamous cell carcinoma and oral squamous cell carcinoma. Traditionally, cancer susceptibility in DC has been largely attributed to telomere shortening and the resulting genomic instability; however, this explanation does not fully account for the heterogeneity observed across different genetic subtypes and clinical phenotypes. In this review, we systematically integrate three key mechanisms through which dyskerin dysfunction contributes to DC-associated carcinogenesis: disruption of telomere homeostasis, defects in selective translation regulation dependent on RNA pseudouridylation, and progressive impairment of T-cell-mediated immune surveillance. We highlight how DKC1 deficiency leads to insufficient rRNA pseudouridylation, selectively affecting the translation of internal ribosome entry site (IRES)-dependent transcripts, thereby attenuating the stress-induced expression of critical tumor suppressor proteins. In parallel, evidence from patient cohort studies is discussed to support a potentially dominant role of immunodeficiency in tumor development. Finally, we propose that future studies on DC and short telomere syndromes should emphasize genetic stratification and long-term clinical outcomes to refine cancer risk assessment and optimize preventive and therapeutic strategies.