Phosphorylated CtIP Functions as a Co-factor of the MRE11-RAD50-NBS1 Endonuclease in DNA End Resection
0301 basic medicine
MRE11 Homologue Protein
0303 health sciences
DNA End-Joining Repair
Endodeoxyribonucleases
10061 Institute of Molecular Cancer Research
DNA Helicases
Nuclear Proteins
610 Medicine & health
Cell Cycle Proteins
Recombinant Proteins
Acid Anhydride Hydrolases
3. Good health
1307 Cell Biology
DNA-Binding Proteins
03 medical and health sciences
DNA Repair Enzymes
Multiprotein Complexes
1312 Molecular Biology
570 Life sciences; biology
Humans
DNA Breaks, Double-Stranded
Phosphorylation
Carrier Proteins
Homologous Recombination
DOI:
10.1016/j.molcel.2016.10.017
Publication Date:
2016-11-23T21:16:41Z
AUTHORS (4)
ABSTRACT
To repair a DNA double-strand break (DSB) by homologous recombination (HR), the 5'-terminated strand of the DSB must be resected. The human MRE11-RAD50-NBS1 (MRN) and CtIP proteins were implicated in the initiation of DNA end resection, but the underlying mechanism remained undefined. Here, we show that CtIP is a co-factor of the MRE11 endonuclease activity within the MRN complex. This function is absolutely dependent on CtIP phosphorylation that includes the key cyclin-dependent kinase target motif at Thr-847. Unlike in yeast, where the Xrs2/NBS1 subunit is dispensable in vitro, NBS1 is absolutely required in the human system. The MRE11 endonuclease in conjunction with RAD50, NBS1, and phosphorylated CtIP preferentially cleaves 5'-terminated DNA strands near DSBs. Our results define the initial step of HR that is particularly relevant for the processing of DSBs bearing protein blocks.
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