title: Transcriptional repressor ZBTB1 promotes chromatin remodeling and translesion DNA synthesis.
abstract: Timely DNA replication across damaged DNA is critical for maintaining genomic integrity. Translesion DNA synthesis (TLS) allows bypass of DNA lesions using error-prone TLS polymerases. The E3 ligase RAD18 is necessary for proliferating cell nuclear antigen (PCNA) monoubiquitination and TLS polymerase recruitment; however, the regulatory steps upstream of RAD18 activation are less understood. Here, we show that the UBZ4 domain-containing transcriptional repressor ZBTB1 is a critical upstream regulator of TLS. The UBZ4 motif is required for PCNA monoubiquitination and survival after UV damage. ZBTB1 associates with KAP-1, a transcriptional repressor whose phosphorylation relaxes chromatin after DNA damage. ZBTB1 depletion impairs formation of phospho-KAP-1 at UV damage sites and reduces RAD18 recruitment. Furthermore, phosphorylation of KAP-1 is necessary for efficient PCNA modification. We propose that ZBTB1 is required for localizing phospho-KAP-1 to chromatin and enhancing RAD18 accessibility. Collectively, our study implicates a ubiquitin-binding protein in orchestrating chromatin remodeling during DNA repair.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Donniphat
authors.initials: D
authors.lastname: Dejsuphong
authors.affiliation: Blais Proteomic Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Adelmant
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Ceccaldi
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yang
authors.affiliation: Blais Proteomic Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: alan_dandrea@dfci.harvard.edu.
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D002470:Cell Survival; D002645:Chickens; D042002:Chromatin Assembly and Disassembly; D004247:DNA / Q000096:biosynthesis*; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
chemical_list: D004247:DNA; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D012097:Repressor Proteins; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases; C485954:RAD18 protein, human; C570228:ZBTB1 protein, human; C101116:TRIM28 protein, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases