Bridging the gap: A family of novel DNA polymerases that replicate faulty DNA

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Abstract
DNA replication can be likened to a car travelling down a long highway. Normally the road is paved smooth, but, as often occurs during travel, the road sometimes contains bumps and roadblocks. Such is the case for the replication machinery as it travels down DNA. While DNA damaged by natural and manmade agents normally is repaired by a multitude of repair pathways, some lesions inevitably escape repair and, as a result, are encountered by the DNA replication machinery. Many of the lesions cannot be bypassed by the replicative DNA polymerases and will lead to cell death if not overcome. Just how cells handle these road blocks has been a longstanding problem. Upon encountering a lesion, the replicative polymerase may dissociate from DNA, leaving a gap in the newly synthesized strand. Such a gap could be filled in by a recombinational mechanism (1) or by a “copy choice” type of DNA synthesis (2). Because both of these mechanisms use information from the undamaged sister duplex to fill in the gap, they are relatively error-free. However, replication of damaged DNA also can occur by synthesis across from the lesion in the template strand. In this case, a specialized replication complex inserts a random nucleotide across from the lesion and continues synthesis beyond the lesion. This process is usually mutagenic and is best exemplified by the Escherichia coli SOS system in which the complex of UmuC and UmuD′ proteins interacts with DNA polymerase III (PolIII) holoenzyme to promote damage bypass. Until recently, the prevailing notion for UmuC-UmuD′ action has been that it overrides the normally high fidelity of PolIII, enabling PolIII to insert a nucleotide across from the lesion and to replicate past the lesion (3). UmuC belongs to a protein family that includes E. coli DinB, Saccharomyces cerevisiae Rev1 and Rad30, …