Understanding Molecular Basis for Cancer Origins
Molecular oncology, relates to cancer formation, growth, metastasis, and treatment, is a rapidly progressing field. There are more than a hundred distinct types of cancers, which can vary substantially in their behavior and response to treatment. Malignant tumors’ ability to invade and metastasize makes cancer fearful because of resistance to treatment.
Most cancers fall into one of the following main groups: carcinomas, sarcomas, gliomas, blastomas and leukemias or lymphomas. Cancers develop from a single cell that starts to proliferate abnormally, and the fundamental feature of cancer is tumor clonality.
Chromatin Folding Around Histones
In human cells, the long strands of genomic deoxyribose nucleic acid (DNA) are wrapped around histone proteins and organized in cells as chromatin. This chromatin DNA must be read out for various cellular functions and copied for the next cell division (DNA replication) while maintaining integrity.
The fate of a cell is not just decided by the genetic code but also by the nature of the 3D organization of the protein-bound DNA, known as chromatin. Modulation of chromatin is critical for cellular proliferation and it is not surprising that alteration of chromatin structure is often observed in cancer cells. These complexes typically contain about twice as much protein as DNA.
The major proteins of chromatin are the histones, which are small proteins containing a high proportion of basic amino acids (arginine and lysine). Chromatin consists of a repetitive nucleoprotein complex, the nucleosome and this particle comprises a histone octamer, with two copies of each of the four core histones H2A, H2B, H3 and H4, wrapped by 147 base pairs of DNA.
The nucleosome is the basic unit of chromatin and is a DNA-protein structure in which negatively charged genomic DNA is tightly attached around a positively charged octamer of histone proteins. The nucleosomes are folded with the aid of linker histone H1 and non‐histone proteins into an ordered, compact nucleoprotein complex. However, it is the histone tails that critically regulate chromatin compaction and function.
X-ray studies of the nucleosome structure have shown that the basic histone N-terminal tails extend from the double strand DNA and contact adjacent histone N-terminal tails. The core histones are characterized by the presence of a structurally conserved motif called histone-fold domain and the dynamic histone-fold extensions, named histone tails, which highly regulate the nucleosome stability.
The positively charged histone tails provide the necessary driving force for folding by mediating favorable inter nucleosomal interactions and screening DNA repulsion. Modifications that change the positive charge of histones may disrupt the electrostatic interaction between DNA and the histone octamer, thereby interfering with the nucleosome structure. In this way, DNA can be detached from the histone complex and accessed by other proteins such as transcription factors or DNA repair machinery.
This is a complex mechanism by which histone modification regulates chromosome structure, gene regulation, DNA replication, and DNA damage response in the cell are interconnected with chromatin remodelers.