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The Transcription Factor TFII-I Promotes DNA Translesion Synthesis and Genomic Stability

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      Translesion synthesis (TLS) enables DNA replication through damaged bases, increases cellular DNA damage tolerance, and maintains genomic stability. The sliding clamp PCNA and the adaptor polymerase Rev1 coordinate polymerase switching during TLS. The polymerases Pol η, ι, and κ insert nucleotides opposite damaged bases. Pol ζ, consisting of the catalytic subunit Rev3 and the regulatory subunit Rev7, then extends DNA synthesis past the lesion. Here, we show that Rev7 binds to the transcription factor TFII-I in human cells. TFII-I is required for TLS and DNA damage tolerance. The TLS function of TFII-I appears to be independent of its role in transcription, but requires homodimerization and binding to PCNA. We propose that TFII-I bridges PCNA and Pol ζ to promote TLS. Our findings extend the general principle of component sharing among divergent nuclear processes and implicate TLS deficiency as a possible contributing factor in Williams-Beuren syndrome.

      Author Summary

      DNA translesion synthesis (TLS) allows the DNA replication machinery to replicate past damaged bases, thus increasing cellular tolerance for DNA damage and maintaining genomic stability. Suppression of TLS is expected to enhance the efficacy of the anti-cancer drug, cisplatin. TLS employs a special set of DNA polymerases, including Pol ζ. The TLS polymerases are also involved in somatic hypermutation and proper immune response in mammals. Thus, it is critical to understand the underlying mechanisms of TLS. In this study, we have discovered the transcription factor TFII-I as a new Pol ζ-binding protein in human cells. We show that TFII-I is indeed required for TLS and DNA damage tolerance. We further delineate the mechanism by which TFII-I contributes to TLS. Our study significantly advances the molecular understanding of TLS, and provides a fascinating example of component sharing among disparate nuclear processes. Finally, because one copy of the TFII-I gene is deleted in Williams-Beuren syndrome (WBS), our work implicates TLS deficiency as a potential causal factor of this human genetic disorder.

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      Most cited references 46

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      Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.

      DNA damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death. Damage to DNA induces several cellular responses that enable the cell either to eliminate or cope with the damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations. These DNA damage response reactions include: (a) removal of DNA damage and restoration of the continuity of the DNA duplex; (b) activation of a DNA damage checkpoint, which arrests cell cycle progression so as to allow for repair and prevention of the transmission of damaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes in the transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavily damaged or seriously deregulated cells. DNA repair mechanisms include direct repair, base excision repair, nucleotide excision repair, double-strand break repair, and cross-link repair. The DNA damage checkpoints employ damage sensor proteins, such as ATM, ATR, the Rad17-RFC complex, and the 9-1-1 complex, to detect DNA damage and to initiate signal transduction cascades that employ Chk1 and Chk2 Ser/Thr kinases and Cdc25 phosphatases. The signal transducers activate p53 and inactivate cyclin-dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S checkpoint), DNA replication (the intra-S checkpoint), or G2 to mitosis (the G2/M checkpoint). In this review the molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed.
        • Record: found
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        Y-family DNA polymerases and their role in tolerance of cellular DNA damage.

        The past 15 years have seen an explosion in our understanding of how cells replicate damaged DNA and how this can lead to mutagenesis. The Y-family DNA polymerases lie at the heart of this process, which is commonly known as translesion synthesis. This family of polymerases has unique features that enable them to synthesize DNA past damaged bases. However, as they exhibit low fidelity when copying undamaged DNA, it is essential that they are only called into play when they are absolutely required. Several layers of regulation ensure that this is achieved.
          • Record: found
          • Abstract: found
          • Article: not found

          Principles of ubiquitin and SUMO modifications in DNA repair.

          With the discovery in the late 1980s that the DNA-repair gene RAD6 encodes a ubiquitin-conjugating enzyme, it became clear that protein modification by ubiquitin conjugation has a much broader significance than had previously been assumed. Now, two decades later, ubiquitin and its cousin SUMO are implicated in a range of human diseases, including breast cancer and Fanconi anaemia, giving fresh momentum to studies focused on the relationships between ubiquitin, SUMO and DNA-repair pathways.

            Author and article information

            [1 ]Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
            [2 ]Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
            [3 ]Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America
            [4 ]Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
            [5 ]Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York, United States of America
            SUNY Stony Brook, United States of America
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: FJF DJC PZ DAB HY. Performed the experiments: FJF KH KRF CY NW RW. Analyzed the data: FJF KH KRF CY NW RW HY. Wrote the paper: HY.

            Role: Editor
            PLoS Genet
            PLoS Genet
            PLoS Genetics
            Public Library of Science (San Francisco, USA )
            June 2014
            12 June 2014
            : 10
            : 6
            24922507 4055408 PGENETICS-D-13-01993 10.1371/journal.pgen.1004419

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Pages: 12
            This research was supported in part by grants from Cancer Prevention and Research Institute of Texas (RP110465-P1 to DJC and RP110465-P3 to HY), the Welch Foundation (I-1441 to HY), and the Clayton Foundation (to HY). This work was also supported by a grant from the National Institutes of Health (CA139217 to DAB). HY is an Investigator with the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Research Article
            Biology and Life Sciences



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