From repair replication to R-loops in half-a-century

Аннотация

Толық мәтін

Genomic maintenance and the persistence of life require the inherent redundancy of information in the two strands of duplex DNA. Nucleotide excision-repair (NER) was a paradigm-shifting discovery in the early 1960's, in which it was shown that short sequences containing damaged nucleotides could be removed from one of the DNA strands and then replaced by repair replication, using the complementary strand as template. The pathways of base excision-repair and mismatch excision-repair were reported some years later. Now we know of genomic stress responses to multiple types of DNA alterations and their repair, including double-strand breaks and replication fork collisions with transcription complexes. Certain types of lesions in transcribed DNA strands escape detection for global NER, but are sensitively detected by blockage of RNA polymerase, to initiate the sub-pathway of transcription-coupled NER. Some normal DNA sequences and non-canonical dNa structures also block transcription. Damage in the non-template DNA strand can arrest transcription if it generates an R-loop, in which the RNA product threads back to form an RNA-DNA duplex. The R-loop can be lethal, particularly if the arrested RNA polymerase is encountered by a replication fork. We are developing a strategy, utilizing peptide nucleic acid (PNA) to generate stable R-loops in selected genes that are uniquely expressed in tumors but not in normal cells, to make the act of transcription toxic for the tumor cells and their metastases.