Transcriptional regulation of the TFIIH transcription repair components XPB and XPD by the hepatitis B virus x protein in liver cells and transgenic liver tissue

Human hepatitis B virus is a risk factor for the development of hepatocellu lar carcinoma. The hepatitis B virus x protein (HBx) has been shown to inac tivate the p53 tumor suppressor protein and impair DNA repair, cell cycle, and apoptosis mechanisms. Herein we report that HBx represses two component s of the transcription-repair factor TFIIH, XPB (p89), and XPD (p80), both in p53-proficient anal p53-deficient liver cells. This inhibition is observ ed while HBx maintains its transactivation function. Expression of HBx in l iver cells results in down-regulation of endogenous XPB and XPD mRNAs and p roteins; this inhibition is-not observed with other TFIIH subunits, XPA or PCNA. In liver tissue from HBx transgenics, WE and XPD proteins are down-re gulated in comparison to matched normal liver tissue. HBx has been shown to interact with Sp1 transcription factor and affects its DNA binding activit y. Sp1 is essential for the basal promoter activity of XPB in liver cells a nd Drosophila SL2 cells, In the Sp1-deficient SL2 cells, HBx-induced XPB an d XPD inhibition is Sp1-dependent. In summary, our results provide evidence that HBx represses the expression of key TFIIH proteins at least in part t hrough Sp1 elements; this repression may impair TFIIH function in DNA repai r mechanisms.