DNA Repair 2

Avoiding Permanent DNA Damage

When a cell encounters DNA damage, it has a number of responses that help to correct any errors and propagating these errors to progeny cells.  Thus, the cell devotes a number of enzymes to detecting and repairing any lesions in the DNA.  Correcting DNA lesions is more important than fixing errors in transcription or translation because of the relative lifespans of the DNA versus mRNA and protein:  mRNA and protein are both expressed and, while they can be longlived, they are not passed on to progeny.  In contrast, DNA of daughter cells is an exact copy of the mother cell, and these daughter cells will carry any lesions that the mother cell carried as well.  Therefore, to prevent long-lasting mistakes in the DNA, the cell fixes any errors that it may encounter.

One of the first hurdles that the cell encounters when it must maintain its genome is that it must accurately copy it, but it must also perform polymerization of DNA quickly enough to facilitate survival.  Once in a while, DNA polymerase will make a mistake, roughly one in a billion base pairs is misincorporated, which is an astoundingly low rate.  Such a low mutation rate is thanks, in part, to the 3’-to-5’ exonuclease activity of DNA polymerase.  When the enzyme is polymerizing DNA and it accidentally adds the wrong nucleotide, this mistake is detected because DNA polymerase is not able to polymerize efficiently from a misincorporated nucleotide.  When the mistake is detected, the exonucleolytic activity of DNA polymerase kicks in and removes several nucleotides behind the incorrect base.  Then, it reverts to its normal function and continues to replicate the DNA. 

When DNA polymerase δ is replicating the DNA and there is an identified lesion ahead of the replication fork, the cell can choose to bypass the lesion and repair it later.  Such a scenario is called translesion synthesis, which uses an alternate polymerase and is not high fidelity, as DNA polymerase δ.  The process involves the ubiquitination of PCNA (proliferating cell nuclear antigen) and the involvement of a number of factors normally involved in DNA repair, including RAD6 proteins and DNA polymerase η.  More information about this alternative mechanism can be found here.