Role of KAP1 and KRAB-ZNFs in breast cancer

“Role of KAP1 and KRAB-ZNFs in breast cancer”

Eukaryotic genomes are, in general, in a default state of repression, where the vast majority of genes are turned off or silenced. This repression is accomplished largely through packaging DNA into tightly coiled DNA-protein fibers called chromatin by association with histones and other proteins. This means that chromatin must be uncoiled before allowing genes to be accessed by proteins that mediate transcription. One mechanism that regulates chromatin structure is the attachment of chemical groups to the histones. It is now becoming clear that a diverse array of enzymes modify histones and place a range of various chemical modifications, including acetylation, phosphorylation, methylation, and sumoylation. One appealing idea is that the pattern and identity of histone modifications constitute a "code" for specific processes, such as transcription. The histone code is written in proteins, not DNA, it can be heritable and constitutes the basis of epigenetics which is increasingly recognized as an important factor in cancer development.

The main system for studying the mechanisms of transcriptional repression in the lab is KRAB domain containing transcription factors. The KRAB-zinc finger (KRAB-ZNF) superfamily of DNA-binding transcriptional repressors is the largest family of gene silencers encoded in the human genome: Estimates are that of the >700 Cys2-His2 class zinc finger genes, more than 350 contain the highly conserved ~75 amino acid KRAB repression domain. KRAB-ZNF mediated transcriptional silencing requires a direct interaction with an obligate co-repressor KAP1 (TRIM28), which serves as a scaffolding protein for recruitment of repression machinery. KAP1 plays important roles in embryonic development, stem cell self-renewal, chromatin organization, and the DNA damage response, acting as an essential corepressor for KRAB-ZNFs. Given the relevance of developmental cell fate regulators and stem cell pluripotency to cancer pathogenesis, understanding how KAP1 functions in cancer cells might be critical for developing future therapeutic strategies.

We recently showed that KAP1 promotes breast cancer cell proliferation and metastasis. The goals of our research are to elucidate the molecular mechanisms by which KAP1 contributes to cancer progression.

Relevant Publications

1. KAP1 promotes proliferation and metastatic progression of breast cancer cells. Addison JB, Koontz C, Fugett JH, Creighton CJ, Chen D, Farrugia MK, Padon RR, Voronkova MA, McLaughlin SL, Livengood RH, Lin CC, Ruppert JM, Pugacheva EN and Ivanov AVCancer Research 2015 Jan 15;75(2):344-55.

2. White D, Rafalska-Metcalf IU, Ivanov AV, Corsinotti A, Peng H, Lee SC, Trono D, Janicki SM, Rauscher FJ 3rd. The ATM substrate KAP1 controls DNA repair in heterochromatin: Regulation by HP1 proteins and serine 473/824 phosphorylation. Molecular Cancer Research2012 Mar; 10(3):401-14.

3. Functional analysis of KAP1 genomic recruitment. Iyengar S, Ivanov AV, Jin VX, Rauscher FJ, Farnham PJ. Molecular and Cellular Biology. 2011; 31(9):1833-47.

4. Ivanov A, Peng H, Yurchenko V, Negorev D, Fredericks W, Maul G, Sadofsky M, Zhou M-M, Rauscher F, III. PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain which is required for gene silencing. Molecular Cell2007 Dec 14;28(5):823-37.