Deciphering the functional role of Baz2B protein and its role in cancer

• Applicant: Dr. Laura Manelyte-Aldehni
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315563949

Epigenetic therapies targeting mutated chromatin remodelling enzymes emerge as a promising new option in personalized cancer medicine. The target of the epigenetic modifiers is chromatin, with the nucleosomes as the basic packaging unit. Nucleosomes positioned on regulatory elements and their respective posttranslational modifications mask the DNA binding sites of regulatory factors, and hence the activity of the associated DNA dependent processes. Active processes are required to move the histone octamer, placing the binding sites into accessible linker regions, thereby enabling transcriptional activation. Chromatin remodeling enzymes are ATPases that alter nucleosome positions, organize chromatin structure and are required to allow or to restrict the sequence specific binding of proteins to DNA. Emerging data shows that these enzymes play essential roles in development and cellular growth. Cancer genome sequencing studies revealed that epigenetic regulators are frequently mutated in human cancer, with about 93% of cancers having mutated chromatin modifiers. These enzymes are targeted to chromatin with their chromatin reader domains that recognize specific epigenetic modifications of histones and DNA. Mutations occurring in chromatin reader domains are not limited to those causing loss of function. There are three particularly important types of mutations that contribute to cancer progression: (i) gain of function or activating mutations that convert normal genes into oncogenes; (ii) loss of function that inactivate tumor suppressors; (iii) drug-resistance mutations that overcome the (usually) inhibitory effect of a drug on the targeted protein, and the forth type of the mutations switch of function. Chromatin binding domains are drugable and several inhibitors are currently in clinical trials. Bromodomain containing proteins are currently intensively studied because of their pivotal role in cancer and wide variety of chemical compounds, inhibiting bromodomain function are currently synthetized and characterized. I propose to address the functional effect of mutations occurring the bromodomain and full-length Baz2B protein in cancer. Baz2B is often highly mutated in various cancers (melanoma, esophagus, liver, ovary etc.), it has unknown function, but is homologous in overall domain organization to the Baz2A protein. Baz2B is predicted to form a complex with the remodelling enzyme Snf2H, to act as a chromatin remodelling complex. By combining biochemical and cellular methods I will elucidate the functional role of Baz2B in the cell. I will further characterize mutations which occur in cancer and their effect on protein function and how they affect global gene expression. This will enable to (a) shed new light on the molecular mechanisms through which these mutations contribute to a malignant phenotype and (b) to understand the biological role of Baz2B protein in the cell and biochemically characterize it.

• DFG Programme: Research Grants