Design and develop treatment strategies for cancer
11 Mar 2015 NUS professors realized that the fundamental mode of gene silencing plays a very important role in designing and developing treatment strategies for cancer.
Cancer occurs when good proteins (tumour suppressors that supposedly protect us) sleep or bad proteins (oncogenes, which are usually inactive) wake up. Therefore, understanding the fundamental mode of gene silencing or activation is important in designing and developing treatment strategies for cancer.
DNA methylation is a biochemical process, where a methyl group is added mainly to promoter CpG sites, is a major mechanism of epigenetic gene silencing and plays important roles in cell division, development and carcinogenesis.
A team led by Prof Kunchithapadam SWAMINATHAN from the Department of Biological Sciences in NUS discovered that the Transcriptional Repressor Domain (TRD) of MBD1, which recruits several repressor proteins such as MCAF1, HDAC3 and MPG that are essential for gene silencing, is intrinsically disordered and interacts with its binding partners in a selective manner. The team has revealed how MBD1-TRD discriminates different binding partners (see Figure). Thus, this expands their understanding of the mechanisms of gene regulation by MBD1.
This image shows the biological functionalities of MBD1-TRD. (A) The electrostatic architecture of MBD1-TRD is shown as hydrophobic or acidic clusters. Identified interacting residues, based on NMR and ITC studies, are mapped onto MBD1-TRD while interacting with (B) MCAF1D8, (C) HDAC3 and (D) MPG. Residues with peak resonances which disappeared and strongly disappeared are coloured magenta and pink, respectively. The greater the disappearance, the lower the intensity retention value. [Image credit: K SWAMINATHAN]
1. Hameed UF, Lim J, Zhang Q, Wasik MA, Yang D, Swaminathan K. “Transcriptional repressor domain of MBD1 is intrinsically disordered and interacts with its binding partners in a selective manner.” Nature Scientific Reports 4 (2014) 4896.