Deciphering the functional role of Baz2B protein and its role in cancer
Biochemistry
Final Report Abstract
Chromatin remodeling complexes are molecular machines that regulate access to DNA, playing a key role in cellular differentiation, growth and homeostasis. It is therefore not surprising that these proteins have an impact on health and disease in the human organism. Within these complexes, Baz2A and Baz2B act as non-catalytic subunits. While Baz2A has been extensively studied, Baz2B remains relatively unexplored. Our research has made a significant contribution to the characterization of Baz2B. This study reveals the intricate landscape of chromatin remodeling and elucidates the pivotal role of Baz2B in cellular processes. The results highlight the potential importance of Baz2B in driving cancer cell proliferation and open up exciting avenues for further exploration in this field. We have discovered that regions adjacent to the TAM domain of Baz2B contain AT-hook motifs capable of binding to both RNA and DNA. In addition, extensive analyses have confirmed the critical role of both the Baz2B TAM domain and the adjacent AT-hooks in facilitating robust interactions with nucleic acids. Molecular dynamics simulations provided further insight into the electrostatic nature of these interactions, allowing an understanding of the dynamic behaviour of the Baz2B TAM domain and adjacent AT-hooks in the presence of nucleic acids. By studying the bromodomain, which is known to recognise acetylated histone tails, we found that it does not interact directly with DNA in isolation, but there is a possibility for nucleic acid interactions within the context of the complete Baz2B protein. This finding adds to our understanding of bromodomains, which have emerged as therapeutic targets in diseases such as cancer. Our study also look at mutations in the bromodomain of Baz2B that have been associated with human cancers. Through structural and binding analyses, we observed altered thermal stability and binding affinities. This suggests a potentially exploitable mechanism in cancer progression and represents a discovery in the field. This knowledge provides the basis for the development of targeted inhibitors of Baz2B and its counterpart, Baz2A, and offers promising prospects for unravelling the dynamic mechanisms that control our genetic material. In addition, the effect of a modified DNA analogue, 5-(6-azidohex-2-ynyl)cytosine (ahyC), on nucleosome formation was investigated, revealing its compatibility and altered behaviour compared to 5-methylcytosine (mC), providing new insights into the biophysical behaviour of modified DNA and synthetic nucleosome design.
Publications
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Enhanced nucleosome assembly at CpG sites containing an extended 5-methylcytosine analogue. Nucleic Acids Research, 50(11), 6549-6561.
Tomkuvienė, Miglė; Meier, Markus; Ikasalaitė, Diana; Wildenauer, Julia; Kairys, Visvaldas; Klimašauskas, Saulius & Manelytė, Laura
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Biochemical and cellular insights into the Baz2B protein, a non-catalytic subunit of the chromatin remodeling complex. Nucleic Acids Research, 52(1), 337-354.
Breindl, Matthias; Spitzer, Dominika; Gerasimaitė, Rūta; Kairys, Visvaldas; Schubert, Thomas; Henfling, Ramona; Schwartz, Uwe; Lukinavičius, Gražvydas & Manelytė, Laura
