To skip or not to skip: choosing repriming to tolerate DNA damage

Abstract

Accurate DNA replication is constantly threatened by DNA lesions arising from endogenous and exogenous sources. Specialized DNA replication stress response pathways ensure replication fork progression in the presence of DNA lesions with minimal delay in fork elongation. These pathways broadly include translesion DNA synthesis, template switching, and replication fork repriming. Here, we discuss recent advances toward our understanding of the mechanisms that regulate the fine-tuned balance between these different replication stress response pathways. We also discuss the molecular pathways required to fill single-stranded DNA gaps that accumulate throughout the genome after repriming and the biological consequences of using repriming instead of other DNA damage tolerance pathways on genome integrity and cell fitness.

Figure 1.. DNA replication stress response mechanisms.

Replication obstacles (represented by the red triangle) transiently stall fork progression. Replication obstacles can be “tolerated” by three distinct pathways to allow resumption of replication fork progression: translesion synthesis (left), template switching or fork reversal (middle), and repriming (right).

Figure 2.. Mechanisms of repriming and ssDNA gap formation in different organisms.

In E. coli, the DnaG primase, as part of the PriC system, interacts with DnaB and promotes repriming in both the leading and lagging strand (left). In budding yeast, repriming is promoted by the Polα/Primase complex and Ctf4, a replisome factor that bridges the MCM component of the CMG helicase and the Polα/Primase complex (middle). In vertebrates, repriming is ensured by PRIMPOL. How recoupling of leading strand synthesis and the CMG helicase occurs after PRIMPOL-mediated repriming in vivo is unknown.

Figure 3.. Factors influencing the choice between the TLS, fork reversal and repriming.

Dashed lines indicate factors that need more investigation. See text for details.