SETD6 Regulates E2-Dependent Human Papillomavirus Transcription

Abstract

Human papillomaviruses (HPV) cause cervical, anogenital, and oral cancers. Brd4 plays an important role in the HPV life cycle. SETD6 was recently shown to methylate Brd4. The current study demonstrates that methylation of Brd4 by SETD6 in HPV-episomal cells is required for the activation of viral transcription. This study illustrates a novel regulatory mechanism involving E2, Brd4, and SETD6 in the HPV life cycle and provides insight into the multiple roles of Brd4 in viral pathogenesis.

E2F1 methylation by SETD6 regulates SETD6 expression via positive feedback mechanism

“…For example, SETD6 was shown to be essential for memory consolidation, regulation of gene expression patterns, and orderly spine morphology in the rat hippocampus (20). SETD6-mediated mono-methylation of BRD4 at K99 (10) was demonstrated to regulate human papillomavirus (HPV) transcription, genome replication, and segregation by binding of BRD4 to the E2 protein (21).…”

“…In diabetic nephropathy, a chronic complication of diabetes, down-regulation of SETD6 protected the cells from apoptosis and mitochondrial dysfunction (21). Furthermore, SETD6 function has been associated with several cancer types (8,22,23).…”

Focal Adhesion Kinase Binds to the HPV E2 Protein to Regulate Initial Replication after Infection

“…The E2 protein binds to inverted palindrome ACCN 6 GGT sequences at the viral origin of replication (ori) to support genome replication [15]. E2 is regulated by several post-translational modifications (PTMs) [16][17][18][19][20][21][22]; the biological functions of these E2 PTMs can be reviewed in reference [23]. We identified Pyk2, a nonreceptor tyrosine kinase and member of the focal adhesion kinase (FAK) subfamily, to suppress viral replication by binding and phosphorylating the HPV-16 and 31-E2 proteins at tyrosine 131 [24].…”

Methylation of the transcription factor E2F1 by SETD6 regulates SETD6 expression via a positive feedback mechanism

“…For example, SETD6 was shown to be essential for memory consolidation, regulation of gene expression patterns, and spine morphology in the rat hippocampus ( 20 ). SETD6-mediated monomethylation of BRD4 at K99 ( 10 ) was demonstrated to regulate human papillomavirus transcription, genome replication, and segregation by binding of BRD4 to the E2 protein ( 21 ). In diabetic nephropathy, a chronic complication of diabetes, downregulation of SETD6 protected the cells from apoptosis and mitochondrial dysfunction ( 21 ).…”

“…SETD6-mediated monomethylation of BRD4 at K99 ( 10 ) was demonstrated to regulate human papillomavirus transcription, genome replication, and segregation by binding of BRD4 to the E2 protein ( 21 ). In diabetic nephropathy, a chronic complication of diabetes, downregulation of SETD6 protected the cells from apoptosis and mitochondrial dysfunction ( 21 ). Furthermore, SETD6 function has been associated with several cancer types ( 8 , 22 , 23 ).…”