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Cellular redox sensor HSCARG negatively regulates the translesion synthesis pathway and exacerbates mammary tumorigenesis.
Proc Natl Acad Sci U S A ; 116(51): 25624-25633, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31796584
The translesion synthesis (TLS) pathway is a double-edged sword in terms of genome integrity. Deficiency in TLS leads to generation of DNA double strand break (DSB) during replication stress, while excessive activation of the TLS pathway increases the risk of point mutation. Here we demonstrate that HSCARG, a cellular redox sensor, directly interacts with the key protein PCNA in the TLS pathway. HSCARG enhances the interaction between PCNA and the deubiquitinase complex USP1/UAF1 and inhibits the monoubiquitination of PCNA, thereby impairing the recruitment of Y-family polymerases and increasing cell sensitivity to stimuli that trigger replication fork blockades. In response to oxidative stress, disaggregation of HSCARG dimers into monomers and the nuclear transport of HSCARG activate the regulatory function of HSCARG in the TLS pathway. Moreover, HSCARG, which is highly expressed in breast carcinoma, promotes the accumulation of DSBs and mutations. HSCARG knockout PyMT transgenic mice exhibit delayed mammary tumorigenesis compared with that in HSCARG wild-type or heterozygous PyMT mice. Taken together, these findings expand our understanding of TLS regulatory mechanisms and establish a link between the cellular redox status and the DNA damage response (DDR).





Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Aspecto clínico: Etiologia Idioma: Inglês Revista: Proc Natl Acad Sci U S A Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: China