USP1 Regulates Cellular Senescence by Controlling Genomic Integrity

Müge Ogrunc (1, 2) , Ricardo Ivan Martinez-Zamudio (2) , Paul Ben Sadoun (3) , Gregory Dore (2) , Helene Schwerer (3) , Philippe Pasero (4, 1) , Jean-Marc Lemaître (3) , Anne Dejean (2, 1) , O Bischof (2, 1)

1 Ligue Nationale Contre le Cancer - Paris
2 Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis
3 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
4 IGH - Institut de génétique humaine

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.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]

Müge Ogrunc, Ricardo Ivan Martinez-Zamudio, Paul Ben Sadoun, Gregory Dore, Helene Schwerer, et al.. USP1 Regulates Cellular Senescence by Controlling Genomic Integrity. Cell Reports, 2016, 15 (7), pp.1401-1411. ⟨10.1016/j.celrep.2016.04.033⟩. ⟨hal-01319844⟩