Abstract
Ubiquitin modification of proteins plays pivotal roles in the cellular response to DNA damage. Given the complexity of ubiquitin conjugation due to the formation of poly-conjugates of different linkages, functional roles of linkage-specific ubiquitin modification at DNA damage sites are largely unclear. We identify that Lys11-linkage ubiquitin modification occurs at DNA damage sites in an ATM-dependent manner, and ubiquitin-modifying enzymes, including Ube2S E2-conjugating enzyme and RNF8 E3 ligase, are responsible for the assembly of Lys11-linkage conjugates on damaged chromatin, including histone H2A/H2AX. We show that RNF8- and Ube2S-dependent Lys11-linkage ubiquitin conjugation plays an important role in regulating DNA damage-induced transcriptional silencing, distinct from the role of Lys63-linkage ubiquitin in the recruitment of DNA damage repair proteins 53BP1 and BRCA1. Thus, our study highlights the importance of linkage-specific ubiquitination at DNA damage sites, and it reveals that Lys11-linkage ubiquitin modification plays a crucial role in the DNA damage response.
Original language | English (US) |
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Pages (from-to) | 458-472.e5 |
Journal | Molecular cell |
Volume | 66 |
Issue number | 4 |
DOIs | |
State | Published - May 18 2017 |
Keywords
- DNA damage response
- RNF8
- Ube2S
- double strand breaks
- histone H2A/H2AX
- ionizing radiation
- transcription inhibition
- ubiquitin
- ubiquitin lysine 11-linkage
- ubiquitin lysine 63-linkage
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
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