USP1 Regulates Cellular Senescence by Controlling Genomic Integrity

• USP1 repression is a hallmark of oncogene-induced senescence
• USP1 repression induces aberrant FANCD2 chromatin aggregation and replication stress
• USP1 repression induces replication arrest via p53, CDKN1A, ATR, FANCD2, and FANCI
• USP1 repression induces sensitivity to DNA interstrand crosslinker reagents

SummaryOncogene-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 γ-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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