The Mre11/Rad50/Nbs1 complex initiates double-strand break repair by homologous recombination (HR). Loss of Mre11 or its nuclease activity in mouse cells is known to cause genome aberrations and cellular senescence, although the molecular basis for this phenotype is not clear. To identify the origin of these defects, we characterized Mre11-deficient (MRE11) and nuclease-deficient Mre11 (MRE11) chicken DT40 and human lymphoblast cell lines. These cells exhibit increased spontaneous chromosomal DSBs and extreme sensitivity to topoisomerase 2 poisons. The defects in Mre11 compromise the repair of etoposide-induced Top2-DNA covalent complexes, and MRE11 and MRE11 cells accumulate high levels of Top2 covalent conjugates even in the absence of exogenous damage. We demonstrate that both the genome instability and mortality of MRE11 and MRE11 cells are significantly reversed by overexpression of Tdp2, an enzyme that eliminates covalent Top2 conjugates; thus, the essential role of Mre11 nuclease activity is likely to remove these lesions.

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PE"-benzene, room temp, dark, 3 days 4 51 J CHsCN, room temp, dark, 3 days 4 8 °Based on reacted indole. 6 Glc analysis. c Petroleum ether. d We thank K. S. Bhandari for this experiment.reported herein show, however, that the chloramines act mainly as electrophilic chlorinating agents2 in reactions with indole under a variety of conditions. Analogous behavior has been found recently in the reaction of indole with N,lV-dichlorourethan.e'7 Nevertheless, our work provides a facile alternate synthesis of 3-chloroindole (4).8

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