The regulator TP53/P53 Sebagai Regulator Sentral Stabilitas Genom: Struktur, Fungsi, Regulasi, Mutasi, dan Implikasi Klinis

regulator sentral stabilitas genom

Abstract

The tumor suppressor p53, encoded by TP53, is a central regulator of genomic integrity and cellular fate. Through its modular structure, p53 integrates signals from DNA damage, oncogenic stress, hypoxia, replication stress, and metabolic disturbance to coordinate cell-cycle arrest, DNA repair, senescence, or apoptosis. This narrative review integrates evidence on p53 structure and functional domains, MDM2/MDMX-centered regulation, the molecular mechanisms underlying cell-cycle arrest, DNA repair, apoptosis and senescence, major TP53 mutation classes, oncogenic mechanisms, and clinical manifestations. TP53 mutations, particularly in the DNA-binding domain, may cause loss of tumor-suppressive activity, dominant-negative effects, or context-dependent gain-of-function phenotypes. Failure of p53-mediated checkpoint and cell-fate control promotes genomic instability, clonal evolution, tumor progression, and treatment resistance. Germline pathogenic TP53 variants cause heritable TP53-related cancer predisposition, including Li-Fraumeni syndrome, which is characterized by early-onset and multiple primary malignancies. Understanding the structural and functional continuum of TP53 is important for variant interpretation, cancer risk assessment, biomarker development, and therapeutic strategies aimed at restoring or exploiting p53 pathway function.