Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Domenico Roberti
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Julia K Pagan
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Elizabeth Sassani
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Andras Zeke
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, New York, United States; Howard Hughes Medical Institute, New York University School of Medicine, New York, United States
The mammalian FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) mono-ubiquitylates H2A at Lys119 to repress transcription in unstressed cells. We found that the FRRUC is rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of H2A at Lys119, a local decrease of H2A levels, and an increase of H2A.Z incorporation. Both the FRRUC and H2A.Z promote transcriptional repression, double strand break signaling, and homologous recombination repair (HRR). All these events require both the presence and activity of the FRRUC. Moreover, the FRRUC and its activity are required for the proper recruitment of BMI1-RNF2 and MEL18-RNF2, two other ubiquitin ligases that mono-ubiquitylate Lys119 in H2A upon genotoxic stress. Notably, whereas H2A.Z is not required for H2A mono-ubiquitylation, impairment of the latter results in the inhibition of H2A.Z incorporation. We propose that the recruitment of the FRRUC represents an early and critical regulatory step in HRR.
