MUTATIONAL ANALYSIS OF THE DNA HELICASE GENES XPB, XPD, WRN AND BLM IN TUMORS WITH WILD TYPE p53 BUT DEFICIENT IN p53 MEDIATED APOPTOSIS

Abstract

Cancer is essentially a genetic disease caused by a defective control of cell proliferation. The P53 gene is known to regulate the responses of cell growth and death to genotoxic stimuli and to protect cells from malignant transformation. Inactivation of P53 is considered to be the most common genetic event in neoplasms and probably contributes to over 50% of all human cancers. Most human cancers show altered growth regulation mediated by two tumor suppressor proteins, those of the retinoblastoma gene (RB) and the P53 gene, indicating that the loss of both pathways is necessary for tumor development. P53 functions in the cellular response to DNA damage and limits the consequences of uncontrolled mitogenesis by promoting cell cycle arrest or apoptosis. The loss of P53 allows the proliferation of neoplastic cells. DNA helicases function by the biochemical manipulation of nucleic acids and mutations in genes in this gene family are associated with several human genetic disorders. Four genes in this category, XPB and XPD associated with xeroderma pigmentosum, BLM with Bloom Syndrome and WRN with Werner Syndrome, were analyzed in cDNAs derived from tumor cell lines known to be wild type for the P53 gene. It is known that P53 selectively binds to and inhibits the DNA helicase activity of transcription repair complexes and that this activity either modulates DNA repair efficiency or triggers apoptosis. Experimental evidence indicates that mutations in these and other DNA helicase genes could influence P53 mediated apoptosis. The data collected from these cell lines resulted in the detection of six polymorphisms of which only two led to an amino acid change within the gene. It was therefore concluded that it is most likely that other component(s) of the p53 pathway are defective in these cells and that the search for the factors causing a neoplastic response in cells that have intact p53 function will require additional research into the factors governing p53 regulation of cell division.