Abstract
KAP1, linked to cancer, coupled RNA polymerase II (RNA Pol II) gene promoter binding to pause exit.
Major Finding: KAP1, linked to cancer, coupled RNA polymerase II (RNA Pol II) gene-promoter binding to pause exit.
Mechanism: KAP1 maintained RNA Pol II at target gene promoters and acted as a scaffold for transcription factors.
Impact: This study elucidates the molecular mechanism underlying KAP1-mediated transcriptional regulation.
The ubiquitously expressed protein KAP1 (also known as TRIM28) is a transcription regulator that has multiple links to cancer. For example, the gene encoding KAP1 is sometimes amplified in cancer, KAP1 is indispensable for xenograft growth in nude mice, and high expression of KAP1 is negatively associated with survival in patients with cancer. Bacon and colleagues found that proliferation of human colorectal cancer cells depended on KAP1, which localized to specific gene promoters and regulated expression of these genes. Further investigation revealed that KAP1 directly associated with RNA polymerase II (RNA Pol II) at the promoters of target genes, where it regulated promoter-proximal pause release of RNA Pol II to facilitate transcriptional elongation. This KAP1-mediated stimulation of RNA Pol II pause release at specific genes occurred via recruitment of the transcription factor SMAD2, which activated transcription of KAP1-bound genes bearing SMAD2 motifs in their promoter sequences. Targeting of specific genes by KAP1 depended on its previously uncharacterized tandem plant homeodomain–bromodomain (PHD–BD) cassette. Unlike the PHD–BD cassettes of other members of the protein family to which KAP1 belongs, KAP1′s PHD–BD cassette directly interacted with hypoacetylated histone 4 (H4) tails. KAP1 binding to hypoacetylated H4 tails was necessary for recruitment of KAP1 to target-gene promoters and subsequent transcriptional activation of target genes. Once bound to a promoter, KAP1 served as a scaffold for RNA Pol II pause-release factors, the final step in KAP1-directed regulation of target-gene expression. Collectively, this work provides insight into the molecular mechanism by which the cancer-associated protein KAP1 couples RNA Pol II promoter binding and pause release to regulate transcription in cancer cells.
Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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