Mre11–Rad50–Nbs1-dependent processing of DNA breaks generates oligonucleotides that stimulate ATM activity

Ali Jazayeri ^[1] ; Alessia Balestrini ^[1] ; Elizabeth Garner ^[1] ; James E Haber ^[2] ; Vincenzo Costanzo ^[1]
1. [1] London Research Institute
  
  London Research Institute
  
  Reino Unido
2. [2] Brandeis University
  
  Brandeis University
  
  City of Waltham, Estados Unidos
Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 27, Nº. 14, 2008, págs. 1953-1962
Idioma: inglés
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Resumen
- DNA double-strand breaks (DSBs) can be processed by the Mre11–Rad50–Nbs1 (MRN) complex, which is essential to promote ataxia telangiectasia-mutated (ATM) activation. However, the molecular mechanisms linking MRN activity to ATM are not fully understood. Here, using Xenopus laevis egg extract we show that MRN-dependent processing of DSBs leads to the accumulation of short single-stranded DNA oligonucleotides (ssDNA oligos). The MRN complex isolated from the extract containing DSBs is bound to ssDNA oligos and stimulates ATM activity. Elimination of ssDNA oligos results in rapid extinction of ATM activity. Significantly, ssDNA oligos can be isolated from human cells damaged with ionizing radiation and injection of small synthetic ssDNA oligos into undamaged cells also induces ATM activation. These results suggest that MRN-dependent generation of ssDNA oligos, which constitute a unique signal of ongoing DSB repair not encountered in normal DNA metabolism, stimulates ATM activity.