The ATM gene product has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination and cell cycle control. The human ATM protein shows similarity to several yeast and mammalian proteins involved in meiotic recombination and cell cycle progression. Because of the homology of the human ATM to the TEL1 and rad3 genes of yeast, it has been suggested that mutations in the ATM could lead to defective telomere maintenance. During the current funding period, we have shown that the ATM gene influences telomere fusion and telomere length. We demonstrated that altered telomere nuclear matrix interactions and nucleosomal periodicity observed in cells derived from individuals with ataxia telangiectasia could be the reason for telomere erosion. Further we determined that ATM influences telomere movement and that defective telomere clustering could explain the failure of spermatogenesis. Using the Atm knockout mice we showed that ATM inactivation results in aberrant telomere clustering during meiotic prophase and its failure of resolution in Atm null mice is linked to aberrant synapses and meiotic arrest. This is of great interest to determine the mechanism of how the ATM could modulate cellular processes influencing genomic integrity possibly through alterations in telomere chromatin structure. Since telomeres are attached to the nuclear matrix, and the ATM gene influences telomere nuclear matrix interactions, we hypothesize that an alteration in telomere chromatin structure may be responsible for defective telomere movement. To test this hypothesis as to whether altered telomere chromatin structure is a potential cause for defective telomere clustering, we propose to compare telomere chromatin structure in meiocytes of Atm null and control mice. Since alteration in chromatin structure is known to influence gene expression, we compared the expression of genes between Atm null and control mice. We found six expressed sequence tags aberrantly expressed in Atm null mice as compared to the normal control, and we will characterize them with respect to their influence on telomere chromatin structure and ionizing radiation responsiveness. These studies will provide information impacting on understanding how ATM influences telomere chromatin structure, which in turn will help to define the role of ATM in maintaining genome integrity and normal cellular behavior.
| Sharma, Girdhar G; So, Sairei; Gupta, Arun et al. (2010) MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. Mol Cell Biol 30:3582-95 |
| Zeng, Sicong; Xiang, Tao; Pandita, Tej K et al. (2009) Telomere recombination requires the MUS81 endonuclease. Nat Cell Biol 11:616-23 |
