{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBE2A encodes a ubiquitin‐conjugating enzyme (E2) that plays a pivotal role in neural development, as evidenced by a series of studies linking mutations in this gene to a distinct form of X‐linked intellectual disability. Disruptive mutations – including both truncating and missense types – perturb the enzyme’s structure (for example, at the conserved C‐terminus or within critical regions such as helix‐3) and give rise to syndromic features such as seizures, speech impairment, dysmorphic facial characteristics, urogenital anomalies, and other systemic abnormalities. These clinical observations, documented in several independent cohorts, underscore the importance of UBE2A in normal neuronal function and development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, UBE2A functions as a central mediator of ubiquitination‐dependent signaling events that regulate DNA repair, transcription, and cell cycle events. It cooperates with specific E3 ligases – for instance, with RNF168, MDM2, or Parkin, and in partnership with kinases such as CDK9 – to catalyze the monoubiquitination of substrates including histone H2B and proliferating cell nuclear antigen (PCNA), thereby influencing chromatin structure and gene expression. In addition, UBE2A participates in maintaining genomic stability via homologous recombination mechanisms, facilitates proper p53 turnover, and modulates protein homeostasis through interactions with other ubiquitination machinery components. Detailed biochemical and structural studies have further revealed that disease‐associated mutations (e.g. those impairing lysine deprotonation at the catalytic pocket or disrupting interactions with E3 partners) compromise UBE2A’s enzymatic activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in neural development and genome maintenance, dysregulation of UBE2A is implicated in oncogenic processes and cellular stress responses. Upregulated UBE2A expression has been correlated with enhanced DNA damage tolerance, altered chromatin states, and the promotion of cancer stem cell gene expression in ovarian tumors, while acquired mutations in UBE2A during leukemia progression disrupt myeloid differentiation. These findings emphasize that temporal and spatial regulation of UBE2A activity is critical not only for proper neuronal function but also for guarding against chemoresistance and malignant transformation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rafaella M P Nascimento, Paulo A Otto, Arjan P M de Brouwer, et al. 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