Ataxia Telangiectasia Mutated:
Ataxia Telangiectasia Mutated
became of interest to researchers when they discovered that mutations in this
gene caused a disease known as Ataxia Telangiectasia (AT). ATM's link to cancer
stems from the fact that patients with this neurodegenerative also have a
higher predisposition to cancer, specifically lymphomas or leukemia, which is
why researchers are working to better understand how mutations in ATM lead to
the formation of cancer [1].
The ATM gene is located on chromosome 11q22-23 (figure 1), taking up a 150kb region. It encodes 66 exons that produce an mRNA of 13kb. This transcript has also been shown to have many 5'-UTRs as well as several different 3'-UTRs which are thought to be used as a way to regulate the amount of ATM protein. This transcript produces a protein that weighs approximately 370kDa and is important in DNA damage repair [1].
When DNA damage occurs in the cell, there are a variety of pathways that can be activated in order to repair the damage so that further abnormalities do not develop. Cells that develop into tumors usually have some sort of DNA damage that prevents them from being regulated like a normal healthy cell, allowing them to grow uncontrollably. This is why it is crucial to tend to the damage before it accumulates putting the individual at higher risk to contract cancer.
ATM is involved in the repair pathway responsible for fixing DNA double stranded breaks. These types of damage are normal within a cell and are repaired through either homologous recombination (HR), which is important in the S and G2 stages of the cell cycle, or nonhomologous end joining (NHEJ), which is important for developing lymphocytes [2]. When a double stranded break is present, multimeric ATM becomes phosphorylated causing it to dissociate into its active monomeric state. From here ATM can act on other proteins which all work together to resolve the DNA double stranded break. In addition to its role in facilitating DNA repair, ATM also works to control cell-cycle checkpoints which are used to stop the cell from dividing if there is some sort of stress present (i.e DNA damage) [3]. ATM’s role in the double stranded DNA damage response is represented in figure 2 .
The ATM gene is located on chromosome 11q22-23 (figure 1), taking up a 150kb region. It encodes 66 exons that produce an mRNA of 13kb. This transcript has also been shown to have many 5'-UTRs as well as several different 3'-UTRs which are thought to be used as a way to regulate the amount of ATM protein. This transcript produces a protein that weighs approximately 370kDa and is important in DNA damage repair [1].
When DNA damage occurs in the cell, there are a variety of pathways that can be activated in order to repair the damage so that further abnormalities do not develop. Cells that develop into tumors usually have some sort of DNA damage that prevents them from being regulated like a normal healthy cell, allowing them to grow uncontrollably. This is why it is crucial to tend to the damage before it accumulates putting the individual at higher risk to contract cancer.
ATM is involved in the repair pathway responsible for fixing DNA double stranded breaks. These types of damage are normal within a cell and are repaired through either homologous recombination (HR), which is important in the S and G2 stages of the cell cycle, or nonhomologous end joining (NHEJ), which is important for developing lymphocytes [2]. When a double stranded break is present, multimeric ATM becomes phosphorylated causing it to dissociate into its active monomeric state. From here ATM can act on other proteins which all work together to resolve the DNA double stranded break. In addition to its role in facilitating DNA repair, ATM also works to control cell-cycle checkpoints which are used to stop the cell from dividing if there is some sort of stress present (i.e DNA damage) [3]. ATM’s role in the double stranded DNA damage response is represented in figure 2 .
Figure 1: Here is a map of chromosome 11. The red line indicates the position of the ATM gene
Figure 2: ATM and the DNA double stranded break repair pathway. The orange P being attached to the proteins signifies phosphorylation. This figure was taken from [3] and a more detailed explanation can be found by clicking on the figure.
References:
1. Rotman, G., & Shiloh, Y. (1998). ATM: From gene to function. Human molecular genetics, 7(10), 1555-1563. doi:10.1093/hmg/7.10.1555
2. Yamamoto et al. (2012). Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice. Journal of Cell Biology, 198(3), 305-313. doi:10.1083/jcb.201204098
3. McKinnon, P. (2004). ATM and ataxia telangiectasia. EMBO reprots, 5(8), 772-776. doi:10.1038/sj.embor.7400210
2. Yamamoto et al. (2012). Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice. Journal of Cell Biology, 198(3), 305-313. doi:10.1083/jcb.201204098
3. McKinnon, P. (2004). ATM and ataxia telangiectasia. EMBO reprots, 5(8), 772-776. doi:10.1038/sj.embor.7400210
This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison