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Human RNA polymerase II-associated factor complex: dysregulation in cancer

Abstract

Genetic instabilities are believed to be one of the major causes of developing a cancer phenotype in humans. During the progression of cancer, aberrant expression of proteins, either owing to genetic (amplification, mutation and deletion) or epigenetic modifications (DNA methylation and histone deacetylation), contributes in different ways to the development of cancer. By differential screening analysis, an amplification of the 19q13 locus containing a novel pancreatic differentiation 2 (PD2) gene was identified. PD2 is the human homolog of the yeast RNA polymerase II-associated factor 1 (yPaf1) and is part of the human RNA polymerase II-associated factor (hPAF) complex. hPAF is comprised of five subunits that include PD2/hPaf1, parafibromin, hLeo1, hCtr9 and hSki8. This multifaceted complex was first identified in yeast (yPAF) and subsequently in Drosophila and human. Recent advances in the study on PAF have revealed various functions of the complex in human, which are similar to yPAF, including efficient transcription elongation, mRNA quality control and cell-cycle regulation. Although the precise function of this complex in cancer is not clearly known, some of its subunits have been linked to a malignant phenotype. Its core subunit, PD2/hPaf1, is amplified and overexpressed in many cancers. Further, an overexpression of PD2/hPaf1 results in the induction of a transformed phenotype, suggesting its possible involvement in tumorigenesis. The parafibromin subunit of the hPAF complex is a product of the HRPT-2 (hereditary hyperparathyroidism type 2) tumor suppressor gene, which is mutated in the germ line of hyperparathyroidism-jaw tumor patients. This review focuses on the functions of the PAF complex and its individual subunits, the interaction of the subunits with each other and/or with other molecules, and dysregulation of the complex, providing an insight into its potential involvement in the development of cancer.

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Acknowledgements

The authors are supported by grants from the National Institutes of Health (CA78590, CA111294), the US Department of Defense (PC040493, PC04502, OC04110) and the Peter Kiewit Foundation. We thank Drs Ajay P Singh and Subhankar Chakraborty for critical reading and Ms Kristi L Berger for editing the manuscript.

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Correspondence to S K Batra.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Chaudhary, K., Deb, S., Moniaux, N. et al. Human RNA polymerase II-associated factor complex: dysregulation in cancer. Oncogene 26, 7499–7507 (2007). https://doi.org/10.1038/sj.onc.1210582

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