Abstract
DNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168− and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.
Original language | English |
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Article number | 5016 |
Pages (from-to) | 5016 |
Journal | Nature Communications |
Volume | 12 |
Issue number | 1 |
DOIs | |
State | Published - Jul 18 2021 |
Keywords
- Animals
- BRCA1 Protein/genetics
- Cell Nucleus/genetics
- DNA Damage
- DNA/genetics
- Fanconi Anemia Complementation Group N Protein/genetics
- Histones/genetics
- Humans
- Mice
- Protein Binding
- Protein Transport
- Rad51 Recombinase/genetics
- Recombinational DNA Repair
- Tumor Suppressor Proteins/genetics
- Ubiquitin-Protein Ligases/genetics
- Ubiquitination
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Campbell, PhD, K. S. (Director) & Kwok, PhD, T. (Manager)
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Campbell, PhD, K. S. (Director), Font-Burgada, PhD, J. (Director), MacFarlane, PhD, A. (Manager) & Oesterling, BS, J. (Manager)
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Cai, MD, PhD, K. (Director) & Zhang, J. (Manager)
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