Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage

Mammalian cells respond to DNA double‐strand breaks (DSBs) by recruiting DNA repair and cell‐cycle checkpoint proteins to such sites. Central to these DNA damage response (DDR) events is the DNA damage mediator protein MDC1. MDC1 interacts with several DDR proteins, including the MRE11–RAD50–NBS1 (M...

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Bibliographic Details
Published in:EMBO reports 2008-08, Vol.9 (8), p.795-801
Main Authors: Chapman, J Ross, Jackson, Stephen P
Format: Article
Language:English
Subjects:
Acid Anhydride Hydrolases
Adaptor Proteins, Signal Transducing
Amino Acid Motifs
Amino Acid Sequence
Animals
Casein Kinase II - genetics
Casein Kinase II - metabolism
Cell cycle
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Cellular biology
checkpoint
Chromatin
Chromatin - metabolism
CK2
Deoxyribonucleic acid
DNA
DNA Damage
DNA Repair Enzymes - genetics
DNA Repair Enzymes - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Flow Cytometry
HeLa Cells
Humans
Immunoblotting
Immunoprecipitation
Mammals
Mass Spectrometry
MDC1
Mice
Microscopy, Fluorescence
Molecular biology
Molecular Sequence Data
MRE11 Homologue Protein
MRN
NBS1
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Phosphorylation
Protein Binding
Proteins
Scientific Report
Sequence Homology, Amino Acid
Trans-Activators - genetics
Trans-Activators - metabolism
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Summary:Mammalian cells respond to DNA double‐strand breaks (DSBs) by recruiting DNA repair and cell‐cycle checkpoint proteins to such sites. Central to these DNA damage response (DDR) events is the DNA damage mediator protein MDC1. MDC1 interacts with several DDR proteins, including the MRE11–RAD50–NBS1 (MRN) complex. Here, we show that MDC1 is phosphorylated on a cluster of conserved repeat motifs by casein kinase 2 (CK2). Moreover, we establish that this phosphorylation of MDC1 promotes direct, phosphorylation‐dependent interactions with NBS1 in a manner that requires the closely apposed FHA and twin BRCT domains in the amino terminus of NBS1. Finally, we show that these CK2‐targeted motifs in MDC1 are required to mediate NBS1 association with chromatin‐flanking sites of unrepaired DSBs. These findings provide a molecular explanation for the MDC1–MRN interaction and yield insights into how MDC1 coordinates the focal assembly and activation of several DDR factors in response to DNA damage.
ISSN:1469-221X
1469-3178
1469-221X
DOI:10.1038/embor.2008.103