RETRACTED: USP1 Regulates Cellular Senescence by Controlling Genomic Integrity

Abstract

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 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.

Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response

“…However, DDR dysregulation leads to multiple pathological settings: extensive impairment of DDR leads to cancer with uncontrolled cell overgrowth, whereas extensive upregulation may precede neurodegenerative and metabolic diseases with specific cell loss ( Jackson and Bartek, 2009 , Shimizu et al., 2014 ). Several lines of evidence support the important function of USP1 in DDR processes ( Cukras et al., 2016 , Nijman et al., 2005 , Ogrunc et al., 2016 , Sourisseau et al., 2016 ). As DDR markers are highly elevated in human and rodent diabetic islets/β-cells in vitro and in vivo and correlate with β-cell death ( Belgardt et al., 2015 , Himpe et al., 2016 , Nyblom et al., 2009 , Oleson et al., 2014 , Oleson et al., 2016 , Tornovsky-Babeay et al., 2014 ), we sought to determine whether USP1 inhibition would modulate DDR under diabetic conditions.…”

Fanconi Anemia Signaling and Cancer

“…However, in addition to this opposition to activate/monoubiquitinate FANCD2/I, USP1 deubiquitination of FANCI has also been associated with promoting core complex recruitment to the site of DNA damage [38]. Whereas, impaired USP1 function leads to genomic instability [39], and cellular senescence with an excessive accumulation of monoubiquitinated FANCI, FANCD2 and PCNA [40]. Therefore, like many other proteins acting in the FA signaling network (Figure 1), USP1 along with the 22 FA proteins critically contributes to the maintenance of genome stability.…”

Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1

“…Interestingly, although the modifications in each pathway are assembled by distinct enzymes, they are removed by the same deubiquitinase, the USP1-UAF1 complex [6][7][8] . Loss of USP1 function results in an accumulation of monoubiquitinated FANCD2, FANCI and PCNA, genomic instability and a failure to complete the pathways 7,[9][10][11][12] . In addition to these three substrates, USP1 deubiquitinates a number of other substrates including inhibitor of DNA binding proteins 1-4 (ID1-4) which regulate cell differentiation 13 and TBK1 which is involved in viral infection 14 .…”