PCNA Ubiquitylation: Instructive or Permissive to DNA Damage Tolerance Pathways?

Jun Che,Xin Hong,Hai Rao

doi:10.3390/biom11101543

Abstract

DNA lesions escaping from repair often block the DNA replicative polymerases required for DNA replication and are handled during the S/G2 phases by the DNA damage tolerance (DDT) mechanisms, which include the error-prone translesion synthesis (TLS) and the error-free template switching (TS) pathways. Where the mono-ubiquitylation of PCNA K164 is critical for TLS, the poly-ubiquitylation of the same residue is obligatory for TS. However, it is not known how cells divide the labor between TLS and TS. Due to the fact that the type of DNA lesion significantly influences the TLS and TS choice, we propose that, instead of altering the ratio between the mono- and poly-Ub forms of PCNA, the competition between TLS and TS would automatically determine the selection between the two pathways. Future studies, especially the single integrated lesion “i-Damage” system, would elucidate detailed mechanisms governing the choices of specific DDT pathways.

Highlights

Most of these lesions are removed by excision repair pathways, such as nucleotide excision repair (NER) and base excision repair (BER), it is inevitable that some DNA lesions can persist and interfere with the work of DNA polymerases when the cell enters the S phase
The cell uses the so-called DNA damage tolerance (DDT) mechanism to get around these lesions [2]
proliferating cell nuclear antigen (PCNA) ubiquitylation upon DNA damage is triggered by the uncoupling of of DNA

Summary

Hypothesis: Hypothesis

PCNA ubiquitylation upon DNA damage is triggered by the uncoupling of of DNA helicase and stalled replicative polymerases [14]. The ratio of PCNA poly-Ub over is not so different among different lesions, but the competition between TLS and TS mono-Ub is not so different among different lesions, but the competition between TLS determines their usage instead. Increasing evidence suggests that TS takes place mostly at post-replicative ssDNA gaps in budding yeast cells [16,17,18,19] In this case, the kinetic of TS is likely determined by the nucleolytic expansion of small gaps (both from 50 and 30 ) [20,21] and the binding of RPA and Rad (the recombination executor) to ssDNA gaps, which should not be altered drastically with different types of DNA lesions. The kinetics of TLS should vary among different types of lesions

Steps Affect the Kinetics of TLS Potentially

PCNA Mono-Ub Likely Does Not Instruct Which TLS Polymerase to Be Used

Stoichiometry and Dynamics of PCNA Ubiquitylation