Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication.
Mre11 complex promotes repair of DNA double-strand breaks (DSBs). Xenopus Mre11 (X-Mre11) has been cloned, and its role in DNA replication and DNA damage checkpoint studied in cell-free extracts. DSBs stimulate the phosphorylation and 3'-5' exonuclease activity of X-Mre11 complex. This induced phosphorylation is ATM independent. Phosphorylated X-Mre11 is found associated with replicating nuclei. X-Mre11 complex is required to yield normal DNA replication products. Genomic DNA replicated in extracts immunodepleted of X-Mre11 complex accumulates DSBs as demonstrated by TUNEL assay and reactivity to phosphorylated histone H2AX antibodies. In contrast, the ATM-dependent DNA damage checkpoint that blocks DNA replication initiation is X-Mre11 independent. These results strongly suggest that the function of X-Mre11 complex is to repair DSBs that arise during normal DNA replication, thus unraveling a critical link between recombination-dependent repair and DNA replication.
Costanzo
V
V
Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Robertson
K
K
Bibikova
M
M
Kim
E
E
Grieco
D
D
Gottesman
M
M
Carroll
D
D
Gautier
J
J
D000595:Amino Acid Sequence; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002453:Cell Cycle / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002474:Cell-Free System; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D000076228:MRE11 Homologue Protein; D008954:Models, Biological; D008969:Molecular Sequence Data; D009865:Oocytes / Q000737:chemistry / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011485:Protein Binding; D011714:Pyrans; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013141:Spiro Compounds; D014982:Xenopus laevis / Q000235:genetics / Q000502:physiology
D000935:Antifungal Agents; D002843:Chromatin; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D010726:Phosphodiesterase Inhibitors; D011714:Pyrans; D011994:Recombinant Proteins; D013141:Spiro Compounds; C053079:tautomycin; D002110:Caffeine; D000076228:MRE11 Homologue Protein; D010749:Phosphoprotein Phosphatases