期刊
CELL REPORTS
卷 15, 期 7, 页码 1401-1411出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.04.033
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类别
资金
- INCa
- ANR
- Odyssey-RE
- ERC-AdG SUMOSTRESS
- Fondation ARC pour la recherche sur le Cancer
- Association La Ligue National Contre le Cancer LNCC
Oncogene-induced senescence (OIS) is a potent barrier for the transformation of pre-cancerous cells. The molecular pathways involved in the execution of OIS are still incompletely understood, but they include chronic DNA damage signaling and post-translational modifications of key factors. Here, we show that OIS-associated transcriptional downregulation of deubiquitinating enzyme USP1 triggers and maintains a DNA damage checkpoint response with atypical DNA lesions that is dependent on functional FANCD2-FI-ATR-CHK1-p53-CDKN1A signaling. We find that a reduced USP1 level causes aberrant aggregation of its target FANCD2 concomitant with replication stress, accumulation, and colocalization of gamma-H2Ax and p53-binding protein 1 (53BP1) in large and unusual sparse DNA damage foci and an increased number of polyploid cells and cells arrested in G2/M, as well as a sensitization of senescence-bypassing cells to DNA interstrand crosslinking-mediated cell death. Our study identifies USP1 as a key senescence regulator controlling genomic integrity and a promising target for anti-cancer therapy.
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