base damage

Single nucleotide (point) mutations are typically generated by the replication of DNA that has acquired some form of abse damage.

Base damage, in turn, derives from several diverse intracellular mechanisms (spontaneous base damage), as well as extracellular agents (environmental base damage) that alter the chemistry and/or sequence of the nitrogenous bases in DNA.

Collectively, the various known sources of spontaneous base damage are estimated to alter about 25,000 bases per human genome per cell per day out of the 3 billions of bases in the genome. With respect to environmental DNA damage, ultraviolet radiation is a ubiquitous and potent source of DNA damage in skin cells.

Another source is chemical carcinogens, which cause DNA damage in cells that are accessible to them (particularly the aerodigestive tract) after their ingestion, their inhalation or their entry into the body by means of other routes.

The potential for mutations caused by base damage is realized by faulty DNA replication across such lesions. But base damage can also result in permanently arrested DNA replication and/or transcription, leading to cell death.

Indeed, the load of base damage from naturally occurring and environmentally related sources would be incompatible with life unless cells were endowed with specific mechanisms for repairing DNA damage and for maintaining mutations at reasonable levels.

One of the main biological responses to DNA damage is DNA repair - biochemical pathways by which damaged, inappropriate (such as the presence of uracil in DNA), and mispaired bases are restored to their native state.

Base damage repair

Base damage (as well as other types of DNA damage such as strand breaks DNA damage) is believed to result in a signal that leads to various cellular responses in eukaryotic cells. The precise nature of this signal is not well understood, but might involve arrested DNA replication and/or arrested RNA polymerase II transcription.

The signal is transduced through signalling cascades to the ultimate effector responses shown in the figure. These include:

 (a) the activation of cell-cycle-checkpoint pathways that arrest cell-cycle progression, thereby providing increased time for various DNA repair or other cellular response mechanisms to operate;
 (b) the coordinated upregulation of a large number of genes, the function of many of which, and their relationship to cellular survival, remains to be determined;
 (c) pathways for programmed cell death (apoptosis), presumably activated when other cellular response pathways will not be sufficiently efficacious;
 (d) multiple biochemical pathways for the bypass of base damage, often resulting in mutations;
 (e) multiple distinct DNA repair pathways.

The total complement of cellular responses is geared to the particular type of damage sustained, such that not all the effector responses mentioned operate simultaneously.

See also

 DNA mutations
 gene mutations