Abstract
RAP80 (receptor-associated protein 80) is a ubiquitin-binding protein that can specifically recognize and bind to Lys-63-linked polyubiquitin chains, thus targeting the BRCA1-A complex to DNA damage sites. To study the role of RAP80 in vivo, we generated RAP80-deficient mice. The deficient mice are prone to B-cell lymphomagenesis. B-cell lymphomas in RAP80-deficient mice are nearly diploid but harbor clonal chromosome translocations. Moreover, the deficient mice are hypersensitive to ionizing radiation. Repair of ionizing radiation-induced DNA double-strand breaks is impaired in RAP80-deficient mouse embryonic fibroblasts. Mechanistically, loss of RAP80 suppresses recruitment of the BRCA1-A complex to DNA damage sites and abrogates the DNA damage repair process at DNA damage sites. Taken together, these results reveal that RAP80 plays a crucial role in the DNA damage response and in maintaining genomic integrity.
Highlights
RAP80 can bind Lys-63-linked polyubiquitin chains, stabilizing the BRCA1-A complex at DNA damage sites
Because the ATG translation start site is in exon 2, the -geo cassette insertion created a fusion transcript containing a region encoding only the N-terminal 49 residues of RAP80 and -geo, which abolished the transcription and translation of all of the important domains of RAP80, such as the N-terminal ubiquitin-interacting motifs that target it to DNA damage sites
Reconstitution of RAP80 in Rap80Ϫ/Ϫ mouse embryonic fibroblasts (MEFs) facilitated the fading of ubiquitination and ␥H2AX foci. These results indicate that RAP80 is important for the DNA damage repair process and the deubiquitination at DNA damage sites
Summary
RAP80 can bind Lys-63-linked polyubiquitin chains, stabilizing the BRCA1-A complex at DNA damage sites. Results: RAP80-deficient mice are cancer-prone and hypersensitive to ionizing radiation. Conclusion: RAP80 plays a crucial role in the DNA damage response and in maintaining genomic integrity. Repair of ionizing radiation-induced DNA double-strand breaks is impaired in RAP80-deficient mouse embryonic fibroblasts. Loss of RAP80 suppresses recruitment of the BRCA1-A complex to DNA damage sites and abrogates the DNA damage repair process at DNA damage sites. Taken together, these results reveal that RAP80 plays a crucial role in the DNA damage response and in maintaining genomic integrity
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