Inherited Neurological Diseases

Affecting 1 in every 18,000 people, Adrenoleukodystrophy (ALD) is a genetic disease that destroys the myelin sheath surrounding a brain neuron. A brain neuron is an essential cell body that is responsible for muscle contractions and ultimately, our ability to move. Adrenoleukodystrophy is a devastating genetic mutation that affects X-chromosomes in both males and females. However, because males only have one X-chromosome, the outcome is catastrophic.

As our cells divide and our DNA replicates, our telomeres provide a start and an end point for the enzyme DNA polymerase to attach to our chromosomes and replicate our DNA. By using a repeated, non-coding section of DNA as the starting point for this replication, the telomeres allow our cells to replicate without damaging important genes at the attachment point of the replicating enzyme. As this occurs though, our telomere begin to lose base pairs

The main problem with chromosome instability produced by these breaks is the susceptibility to translocations and thus oncogene activation.

When a tumor suppressor gene is effected by a mutation, it loses its control over the cell and the cell does not stop to get inspected. When this happens, the mutation is copied, the cell divides and damage is passed down to the newly formed daughter cells. The mutation then becomes permanent and the now mutated cell will continue to divide and proliferate when it normally would not.

Cancer is a disease caused by an uncontrolled division of abnormal cells. The DNA sequence in cells can be changed as a result of copying errors during replication. If these changes whatever their cause are left uncorrected, both growing and non-growing somatic cells might gain many mutations that they could no longer function. The relevance of DNA damage and repair to the generation of cancer was obvious when it was recognized that everything that causes cancer also cause a change in the DNA sequence. Tumor suppressor genes are protective genes and normally they limit cell growth by monitoring the speed of cell division, repair mismatched DNA and control when a cell dies. When a tumor suppressor gene is mutated cells grow

On December 10, 2015, three profound individuals received the Nobel Prize in chemistry for their work on DNA repair systems. Paul Modrich, Thomas Lindahl, and Aziz Sancar studied how the cell repairs and protects the information held in its DNA; specifically, Paul Modrich focused on DNA mismatch repair. Since DNA constantly replicates, damage and incorrect pairings are expected, but enzymes watch over DNA as it replicates and repair any errors that occur. In the mismatch repair system, enzymes find the mismatch in the copy of DNA, cut the incorrect section out, and replace it with the correct sequence. Paul Modrich’s study of the mismatch repair system has provided the medical field with important information regarding cancer growth and the possibility of a cure.

On September 12, 1016, Belmont University graciously allowed Dr. Katherine Friedman from Vanderbilt University to come and talk to a crowd of students about the tendencies of how deoxyribose double stranded breaks can during cell replication and the elements required to hopefully repair this ordeal. She began the session by discussing what chromosomes are composed of and how they are produced, accompanied by visual and statistical representations. Moving on, she touched on how double strand breaks are a huge threat to a cell's, an organisms, stability. Correspondingly, she described what can cause these breaks; chemical factors, as well as inner cell disruptions during replication that are sometimes hard to remedy. However, she also stated that this breaks can occur on purpose, mostly in the immune system in efforts to make antibodies.

The first stage consists of a mutation of DNA which does not undergo DNA repair (by enzymes) or undergoes faulty DNA repair.

1. Proto-oncogenes and tumor suppression genes are both used to help regulate the cell cycle. Tumor suppression genes produce proteins that inhibit cell division, and proto-oncogenes produce proteins that stimulate cell growth and division. The balance between the activities of these two genes ensure cells are dividing at a suitable rate for their body. Mutations affect these cells in two different ways. When mutation occurs, proto-oncogenes become oncogenes. Oncogenes promote excessive growth and causes the cells to divide excessively, even when it is unnecessary for the cell to keep dividing. When mutation occurs for tumor suppression genes, the tumor suppression genes can become inactive. Because tumor suppression genes inhibit and lessen

To repair mismatched bases, the system has to know which base is the correct one. In order to recognize the parental strand, the characteristic than can be detect isi it is a DNA strand that has been methylated. Once in a while, there will be times when the polymerase would accidentally place the wrong base across the template DNA strand during the replication of DNA. Usually it would detect it mistakes, and correct itself. But, if polymerase failed to fix its mistakes, there are some types of repair enzymes that would scan the DNA strand and proof reed the strand again. However, there might still be a wrongly placed base pair of the new strand compare to the parental strand. Figure 7 in page 15 show the pathways

Failure of overcoming such lesions will cause chromosome duplication failure and may lead to mitotic catastrophe, complex chromosomal rearrangements, and tumorigenesis. Multiple mechanisms are developed by the cells to sense and respond to such type of lesions. In replication fork stalling, the cell senses the lesion with replication protein A as well as its downstream factors. At the same time, the Fanconi Anemia proteins facilitates the interstrand crosslinking lesions (see next section, 1.3.2). Particularly, FANCM, together with its binding partners MHFs and FAAP24, will facilitate the activation of ATR/CHK1 signaling pathway for further repair. After proper responses to the replication stresses, the stalled or collapsed replication forks will be restarted (Collis et al., 2008; Wang et al., 2013). Under certain circumstances, single strand DNA gaps will remain on the DNA strand even though the stalled replication forks are successfully overcome, in which a DNA clamp, proliferating cell nuclear antigen (PCNA), and other proteins will function in a postreplication repair to further fix the damages left (Tian et al.,

Werner syndrome is an autosomal recessive genetic condition associated with the WRN gene (7). The WRN gene found on chromosome 8 encodes a protein called Werner (4). The Werner protein works as a helicase assisting in the unwinding of DNA. The helicase belongs to the RecQ helicase family and assists in DNA repair, maintenance and regulation of telomeres (4). The Werner protein also functions as an exonuclease that also assists in DNA repair, replication and transcription (4). The Werner protein has been found to be essential in repairing double stranded breaks during replication fork stalling (3). The WRN gene and Werner protein demonstrate an essential role in the integrity and stability of DNA.

For better understanding of Base excision repair pathway and to maintain the continuity of the real succession there is a little description of the cell cycle and its conjunction to this pathway.

DNA replication; RNA synthesis; cell wall synthesis and protein synthesis have been identified as possible targets for cellular disruption which is undoubtedly a complex process.

Point Mutation: is a nucleotide base change in the DNA that is caused by mutation. It may result in the loss, addition or substitution of a nucleotide. Where a single nucleotide base in the DNA strand is altered.