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

Abstract

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.