1.15.18 DNA Damage Tolerance Definition

DNA Damage Tolerance Definition is a description of a set of cellular mechanisms that allow DNA replication to proceed past an unrepaired lesion on the template strand, without first removing or correcting that lesion, thereby permitting replication to continue in the presence of damage that would otherwise block the advancing replication machinery, at the cost of potentially introducing sequence alterations at or near the site of the bypassed lesion.

Conceptual Basis

Bypass Rather Than Repair

DNA damage tolerance is conceptually distinct from DNA repair: repair pathways act to physically remove or correct a lesion and restore the original DNA structure, whereas damage tolerance mechanisms leave the underlying lesion in place and instead allow replication to proceed across or around it, deferring the eventual resolution of the lesion itself to a later time.

A Response to Replication Blockage

DNA damage tolerance mechanisms are specifically engaged when a replication fork encounters a lesion capable of blocking normal progression of the replication machinery, providing a means for the cell to complete replication of the affected region despite the continued presence of the unresolved lesion.

Principal Mechanisms

Translesion Synthesis

Translesion synthesis involves the use of specialized DNA polymerases capable of inserting a nucleotide opposite a damaged template base and continuing synthesis past the lesion, in place of the normal replicative polymerase, which is typically unable to proceed across such lesions; because these specialized polymerases operate with reduced accuracy compared to the normal replicative polymerase, translesion synthesis carries an increased likelihood of introducing an incorrect nucleotide at the site of the lesion.

Template Switching

Template switching involves temporarily using the newly synthesized strand of the sister chromatid as an alternative template to bypass the damaged region, rather than continuing synthesis directly across the lesion itself, allowing the affected region to be completed using undamaged sequence information before the original template is later reconciled with the lesion still present.

Consequences of Damage Tolerance

Completion of Replication Despite Unresolved Damage

The immediate functional benefit of DNA damage tolerance is the ability of a cell to complete replication of its genome even when lesions remain present on the template strand, avoiding the more severe consequence of persistent fork stalling or collapse that could otherwise result from an unresolved blocking lesion.

Increased Risk of Sequence Alteration

Because damage tolerance mechanisms, particularly translesion synthesis, operate with reduced fidelity compared to normal replication, use of these mechanisms is associated with an increased probability that the sequence synthesized at or near the site of the original lesion will differ from what would have resulted had the lesion been fully repaired prior to replication.

Deferred Resolution of the Underlying Lesion

The Original Lesion Remains to Be Addressed

Because damage tolerance mechanisms bypass a lesion without removing it, the original DNA lesion typically remains present in the genome following tolerance-mediated replication and must still be addressed by an appropriate DNA repair pathway at a subsequent point, distinguishing the temporary bypass function of tolerance from the permanent resolution function of repair.

Relationship to Genome Instability

A Trade-Off Between Replication Continuity and Fidelity

DNA damage tolerance represents a cellular trade-off, favoring continued replication over strict sequence fidelity at the specific sites where lesions are bypassed, and the reduced fidelity characteristic of these bypass mechanisms, particularly translesion synthesis, contributes to the accumulation of point mutations associated with genome instability, especially under conditions of substantial replication stress in which reliance on tolerance mechanisms is increased.