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

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.

Automated summary

Lesions in DNA that escape repair can block DNA replication, which is handled during the S/G2 phases by damage tolerance mechanisms such as TLS and TS. The ubiquitylation of PCNA plays a critical role in determining the choice between TLS and TS pathways, with competition between the two pathways being influenced by the type of DNA lesion.