Mre11p regulates the onset of Telomeric recombination.
Immanual Joseph (1), Mark Tidwell (1), Bibo Li (2), and Arthur J. Lustig (1)
(1) Department of Biochemistry, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA, USA; (2) Laboratory of Molecular Parasitology, The Rockefeller University, New York, NY, USA.
Mre11p is a multifaceted protein that acts in complex with Rad50p and Xrs2p (the MRX complex) in all eukaryotes including the budding yeast Saccharomyces cerevisiae. Amoung the many functions of MRX is its involvement in homologous and telomeric recombination. Whether these functions are mediated through checkpoint signaling or Mer11 nuclease activity remains unknown. The elimination of the RNA component of telomerase results in senescence (cell cycle arrest) followed by the accumulation of survivors formed by the Mre11p-dependent amplification of TG(1-3) repeats (Type II) and Mre11p-independent tandem amplification of sub-telomeric Y' elements (Type I). A novel allele or Mre11, A470T, was identified in our laboratory in a screen for mutations that influence telomeric rapid deletion. This mutation falls in a highly conserved 14 amino acid stretch extending from amino acid 470 to 483. The neural net program NetPhos predicts a high probability of A470T phosphorylation. This is a intriguing result given that Mre11 undergoes phosphorylation in response to DNA damage. While double knockouts of MRE11 and TLC1 increases the rate senescence by suppressing recombination, we show here that the A470T-tlc1 double mutant bypasses the characteristic senescence phenotype of tlc2 cells. We demonstrate that this effect is mediated through induction of promiscuous Type 1 recombination before cell arrest. We are now determining whether this is the consequence of a generalized increase in repeat element recombination or a telomere-specific process and the possible role of A470T induced DNA damage. We are investigating whether these effects are mediated through promiscuous signaling or end processing. Ultimately, these studies should offer insight into the recombination mechanisms that overcome senescence and mediate the oncogenic state. This study was supported through grants from the NIH and NSF.
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