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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Antibodies / immunology
-
Antibodies / pharmacology
-
BRCA1 Protein / genetics*
-
BRCA1 Protein / immunology
-
BRCA1 Protein / metabolism*
-
Breast Neoplasms / genetics*
-
Breast Neoplasms / metabolism
-
Breast Neoplasms / pathology
-
Cell Cycle Proteins / genetics*
-
Cell Cycle Proteins / immunology
-
Cell Cycle Proteins / metabolism*
-
Cells, Cultured
-
DNA Damage / physiology
-
DNA Repair / physiology
-
DNA-Binding Proteins
-
Embryonic Stem Cells / cytology
-
Female
-
Fibroblasts / cytology
-
Genomic Instability / physiology*
-
Histone Chaperones
-
Mice
-
Mice, Knockout
-
Rabbits
-
Transcription Factors / genetics*
-
Transcription Factors / immunology
-
Transcription Factors / metabolism*
-
Ubiquitin / metabolism
Substances
-
Antibodies
-
BRCA1 Protein
-
Cell Cycle Proteins
-
DNA-Binding Proteins
-
Histone Chaperones
-
Rap80 protein, mouse
-
Transcription Factors
-
Ubiquitin