Biological Interactions:
The study of protein-protein interactions is crucial when researching biological systems because it can help us better understand how processes in the cell are carried out. Nowadays the use of ‘interactomics’ is becoming popular when the function of proteins within a cell. Interactomics is a termed used to describe the study of how molecules are linked to each other within a living organism and what that interaction results in [1].
The ATM protein was found to be a part of a large interaction network comprised of many proteins by using the STRING database. This large interaction network was expected as ATM is a part of a diverse set of cellular processes as described on the gene ontology page. Some of these proteins, such as BRCA1, are previously known to be a part of the DNA repair pathway so their involvement in the ATM network does not come as a surprise. Some of these proteins, such as TP53 are also responsible for inducing apoptosis, the cell death pathway which ATM is also associated with. ATM’s role in other processes can be understood by studying this interaction network and seeing what different types of proteins are involved. This network can be useful in trying to determine the ramifications of disruptions in the ATM gene as well.
The ATM protein was found to be a part of a large interaction network comprised of many proteins by using the STRING database. This large interaction network was expected as ATM is a part of a diverse set of cellular processes as described on the gene ontology page. Some of these proteins, such as BRCA1, are previously known to be a part of the DNA repair pathway so their involvement in the ATM network does not come as a surprise. Some of these proteins, such as TP53 are also responsible for inducing apoptosis, the cell death pathway which ATM is also associated with. ATM’s role in other processes can be understood by studying this interaction network and seeing what different types of proteins are involved. This network can be useful in trying to determine the ramifications of disruptions in the ATM gene as well.
Discussion:
By using the STRING database, it was found that sirtuin 1(SIRT1) was a part of ATM’s interaction network. This was interesting as SIRT1 is a deacetylase responsible for regulating apoptosis through its interaction with TP53 (p53) [2]. It has been previously shown that, upon ATM activation, SIRT1 activity goes down, which allows for the proper activation of TP53 and therefore proper cell death [3]. It could be speculated that cells lacking ATM do not properly regulate SIRT1 levels, which could result in difficulties activating apoptosis. This is important because patients with CLL and an 11q- (see homepage) are missing a copy of ATM and are at higher risk for developing a mutation at the other allele which results in a lower sensitivity to chemotherapeutics [4]. Knowing this, it would be beneficial to look to see how SIRT1 levels are affected in CLL patients harboring an 11q-. The proposed future directions were motivated by these facts, and, therefore, involve looking for closely at SIRT1 levels in ATM deficient cells
References:
1. Kiemer, L., & Cesareni, G. (2007). Comparative interactomics: comparing apples and pears? Trends in Biotechnology, 25(10), 448-454. doi:10.1016/j.tibtech.2007.08.002
2. Ingeborg van Leeuwen, Sonia Lain, Chapter 5 Sirtuins and p53, In: George F. Vande Woude and George Klein, Editor(s), Advances in Cancer Research, Academic Press, 2009, Volume 102, Pages 171-195, ISSN 0065-230X, ISBN 9780123744371, 10.1016/S0065-230X(09)02005-3.
3. Yuan, J., Luo, K., Liu, T., & Lou, Z. (2012). Regulation of SIRT1 activity by genotoxic stress. Genes and development, 26, 791-796. doi:10.1101/gad.188482.112
4. Austen, B., Skowronska, A., Baker, C., Powell, J. E., Gardiner, A., Oscier, D., . . . Stankovic, T. (2007). Mutation Status of the Residual ATM Allele Is an Important Determinant of the Cellular Response to Chemotherapy and Survival in Patients With Chronic Lymphocytic Leukemia Containing an 11q Deletion. Journal of Clincial Oncology, 25(34), 5448-5457. doi:10.1200/JCO.2007.11.2649
2. Ingeborg van Leeuwen, Sonia Lain, Chapter 5 Sirtuins and p53, In: George F. Vande Woude and George Klein, Editor(s), Advances in Cancer Research, Academic Press, 2009, Volume 102, Pages 171-195, ISSN 0065-230X, ISBN 9780123744371, 10.1016/S0065-230X(09)02005-3.
3. Yuan, J., Luo, K., Liu, T., & Lou, Z. (2012). Regulation of SIRT1 activity by genotoxic stress. Genes and development, 26, 791-796. doi:10.1101/gad.188482.112
4. Austen, B., Skowronska, A., Baker, C., Powell, J. E., Gardiner, A., Oscier, D., . . . Stankovic, T. (2007). Mutation Status of the Residual ATM Allele Is an Important Determinant of the Cellular Response to Chemotherapy and Survival in Patients With Chronic Lymphocytic Leukemia Containing an 11q Deletion. Journal of Clincial Oncology, 25(34), 5448-5457. doi:10.1200/JCO.2007.11.2649
This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison