December 1, 2014
A stitch in time saves nine, goes the old saying. And here a team of scientists at Indian Institute of Science study RAGs (recombination activating genes) to understand the stitching and unstitching of the DNA, which in certain ways leads to genomic instability and cancer.
The RAG complex consists of two genes, RAG1 and RAG2. These genes produce the RAG proteins – RAG1 and RAG2 — which are expressed in the B and T cells of our immune system. The B and T cells help in locating and dealing with foreign substances that enter our bodies like bacteria and other microbes. The cells can recognise foreign bodies using proteins on their surfaces. The RAG gene complex helps in the generation of these surface proteins.
The high number of surface proteins that need to be produced sometimes leads to genomic instability and “chromosomal translocations” – rearrangement of bits of the chromosome, which can lead to incorrect arrangement of genes. This can lead to diseases like lymphoma and leukemia.
In a previous study, Dr. Sathees C Raghavan and Rupa Kumari showed that RAG proteins cleave DNA when they spot a particular sequence of nucleotides. In this paper, they have focussed on studying the factors that can regulate DNA cleavage efficiency of the RAG proteins. This can improve our understanding of how the DNA cleaving activity of these genes is turned on and off.
They found that apart from the sequence of a particular DNA complex, the sequence of the regions surrounding it are important in determining where the RAG proteins bind and where they cleave. The presence of cytosine and thymine in a single stranded region of the DNA complex dictates the position of nicking. A minimum of two cytosines are required for the RAGs cleavage efficiency. The deletion of certain sequences could result in the loss of sequence specific nuclease activity of RAG but it retains its structure specific nuclease activity.
The further understanding of these factors which regulate the stability of the above mentioned DNA complex could help us decipher the mutations that act as the root causes leading to cancers like lymphoma and leukemia.
The paper has been published online on 14th November in The FEBS Journal. http://onlinelibrary.wiley.com/doi/10.1111/febs.13121/abstract