Abstract
DNA damage is a constant source of stress challenging genomic integrity. To ensure faithful duplication of our genomes, mechanisms have evolved to deal with damage encountered during replication. One such mechanism is referred to as DNA damage tolerance (DDT). DDT allows for replication to continue in the presence of a DNA lesion by promoting damage bypass. Two major DDT pathways exist: error-prone translesion synthesis (TLS) and error-free template switching (TS). TLS recruits low-fidelity DNA polymerases to directly replicate across the damaged template, whereas TS uses the nascent sister chromatid as a template for bypass. Both pathways must be tightly controlled to prevent the accumulation of mutations that can occur from the dysregulation of DDT proteins. A key regulator of error-prone versus error-free DDT is the replication clamp, proliferating cell nuclear antigen (PCNA). Post-translational modifications (PTMs) of PCNA, mainly by ubiquitin and SUMO (small ubiquitin-like modifier), play a critical role in DDT. In this review, we will discuss the different types of PTMs of PCNA and how they regulate DDT in response to replication stress. We will also cover the roles of PCNA PTMs in lagging strand synthesis, meiotic recombination, as well as somatic hypermutation and class switch recombination.
Highlights
Accurate DNA replication is essential for genome stability and cell homeostasis [1,2].DNA damage encountered during replication poses a continuous threat to genomic integrity
ZRANB3 acts as a structure-specific endonuclease that cleaves branched DNA structures, playing roles in DNA damage bypass and in DNA repair (Figure 2) [131]. These results demonstrate that ZRANB3 functions downstream of poly-ubiquitinated proliferating cell nuclear antigen (PCNA) to promote active fork slowing and reversal to protect chromosome integrity in response to replication stress
These results demonstrate that ZRANB3 functions downstream of poly-ubiquitinated PCNA to promote active fork slowing and to protect chromosome integrity in response to replication stress
Summary
Accurate DNA replication is essential for genome stability and cell homeostasis [1,2]. DDR is highly efficient, some DNA lesions may escape repair and interfere with the progression of replication forks In this scenario, cells utilize DNA damage tolerance (DDT) pathways to bypass lesions encountered during replication. PCNA acts as a loading platform for replication factors and proteins involved in cell cycle control and repair [19,20]. These functions of PCNA are largely regulated by post-translational modifications at distinct lysine residues. We will highlight the importance of PCNA ubiquitination and SUMOylation in the regulation of DDT pathways and how they act to maintain genome stability. We will discuss how the misregulation of these pathways can lead to cellular transformation and tumorigenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
