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...
| Glavni autori: | , |
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| Format: | Journal article |
| Jezik: | English |
| Izdano: |
2008
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| _version_ | 1826284818443272192 |
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| author | Chapman, R Jackson, S |
| author_facet | Chapman, R Jackson, S |
| author_sort | Chapman, R |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T01:19:33Z |
| format | Journal article |
| id | oxford-uuid:8fdfa661-fd07-4b7b-885c-486fd0b3f2d1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:19:33Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:8fdfa661-fd07-4b7b-885c-486fd0b3f2d12022-03-26T23:07:28ZPhospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8fdfa661-fd07-4b7b-885c-486fd0b3f2d1EnglishSymplectic Elements at Oxford2008Chapman, RJackson, SMammalian 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. |
| spellingShingle | Chapman, R Jackson, S Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. |
| title | Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. |
| title_full | Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. |
| title_fullStr | Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. |
| title_full_unstemmed | Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. |
| title_short | Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. |
| title_sort | phospho dependent interactions between nbs1 and mdc1 mediate chromatin retention of the mrn complex at sites of dna damage |
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