Abstract：
: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-/H129N) 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-/H129N 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-/H129N 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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Hoa NN,Shimizu T,Zhou ZW,Wang ZQ,Deshpande RA,Paull TT,Akter S,Tsuda M,Furuta R,Tsutsui K,Takeda S,Sasanuma Hdoi
10.1016/j.molcel.2016.10.011subject
Has Abstractpub_date
2016-11-03 00:00:00pages
580-592issue
3eissn
1097-2765issn
1097-4164pii
S1097-2765(16)30634-7journal_volume
64pub_type
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