As the repository of a cell’s genetic blueprint, safeguarding the integrity of chromosomes is of critical importance. DNA damage is happening on an on-going basis, and left unchecked, it could lead to cancer or cell death. Myriad biological mechanisms are devoted to DNA repair in our cells. Base Excision Repair, Mismatch Repair, Double-Strand Break Repair, Cross-Link Repair… The extensive list of DNA repair processes that have been characterized is ever-growing, with many not fully understood yet. However, it is the DNA itself that stores the instructions for conducting all this molecular mending. What happens if the DNA damage disables those very instructions? A number of Chromosomal Instability Syndromes result from such impairment. Here, we will discuss two such syndromes.
Bloom Syndrome is a very rare recessive disorder; both parents must be carriers. Each parent must pass a defective copy of the BLM gene to their child for Bloom Syndrome to manifest fully. The BLM protein is a helicase, meaning it plays a role in unwinding DNA strands. A reduction of the cell’s ability to perform this function impacts other repair proteins that rely on DNA strands to be unwound before they can carry out their tasks. One situation in which the BLM protein plays a critical role is in resolving Holliday Junctions, in which two DNA helices open and combine to form a cross structure. If not unwound with the help of BLM, the DNA tangle might instead be resolved by inappropriate homologous recombination. This can result in structural changes to DNA that introduce defects. One of the most characteristic structural changes seen in the cells of Bloom Syndrome patients is the sister chromatid exchange (SCE), in which sections of the two chromatids of a chromosome switch sides. Techniques which differentially stain the chromatids, like directional Genomic Hybridization can be used to detect the change in SCE rate. The increase can be by more than an order of magnitude.
Nijmegen Breakage Syndrome is also autosomal recessive and is seen in about 1 out of every 100,000 newborns. It is due to lacking a functioning NBN gene, which encodes a protein called nibrin. It forms a complex of five proteins which together function to repair double-strand DNA breaks. The protein complex also serves to alert the cell when it has taken excessive DNA damage, such as from ionizing radiation. Persons with Nijmegen Breakage Syndrome exhibit a high rate of inversions and translocations which mainly affect chromosomes seven and fourteen. Diagnostic confirmation requires detection of deleterious mutations in both copies of the NBN gene.
Many uncharacterized Chromosomal Instability Syndromes exist in the world. Their health impacts can be far-reaching, resulting in malformations, cognitive impairments, higher rates of cancer, reduced fertility, and shortened lifespan. There isn’t always a full understating of the etiology of each condition due to the relatively small number of documented cases and limited resources available for research. Hopefully, modern DNA analysis techniques will continue to unravel the underlying mechanisms of these conditions and supply new options to improve the quality of life of those impacted.