PubMed · 210385
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E Lawrence. 1978-07-20. Replication: twenty-five years after.. https://doi.org/10.1038/274210a0
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To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA-damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents. The difficulty in capitalizing on synthetically lethal interactions in cancer cells is that many potential targets do not possess well-defined small-molecule binding determinates. In this review, we discuss several successful campaigns to identify and leverage small-molecule inhibitors of the DNA repair proteins, from PARP1, a paradigm case for clinically successful small-molecule inhibitors, to coveted new targets, such as RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase.
The RAD51 and RAD52 genes of Saccharomyces cerevisiae are key members of the RAD52 epistasis group required for genetic recombination and the repair of DNA double-stranded breaks. The RAD51 encoded product mediates the DNA strand exchange reaction. Efficient strand exchange is contingent upon the addition of the heterotrimeric single-stranded DNA binding factor replication protein A (RPA) after Rad51 has nucleated onto the single-stranded DNA. However, if the single-stranded DNA is incubated with Rad51 and RPA simultaneously to mimic what may be expected to occur in vivo, the efficiency of strand exchange decreases dramatically, revealing an inhibitory effect of RPA that is distinct from its stimulatory function. Interestingly, the inclusion of Rad52 protein, which has been purified in this study from yeast cells, restores the efficiency of strand exchange. Thus, Rad52 functions as a co-factor for the Rad51 recombinase, acting specifically to overcome the apparent competition by RPA for binding to single-stranded DNA.
TFIIH is a multifunctional RNA polymerase II transcription factor that possesses DNA-dependent ATPase, DNA helicase, and protein kinase activities. Previous studies have established that TFIIH enters the preinitiation complex and fulfills a critical role in initiation by catalyzing ATP-dependent formation of the open complex prior to synthesis of the first phosphodiester bond of nascent transcripts. In this report, we present direct evidence that TFIIH also controls RNA polymerase II activity at a postinitiation stage of transcription, by preventing premature arrest by very early elongation complexes just prior to their transition to stably elongating complexes. Unexpectedly, we observe that TFIIH is capable of entering the transcription cycle not only during assembly of the preinitiation complex but also after initiation and synthesis of as many as four to six phosphodiester bonds. These findings shed new light on the role of TFIIH in initiation and promoter escape and reveal an unanticipated flexibility in the ability of TFIIH to interact with RNA polymerase II transcription intermediates prior to, during, and immediately after initiation.