Levels of p53 govern the hierarchy of DNA damage tolerance pathway usage

Model for p53 level-dependent DDT pathway choices. Identified by key molecular components as outlined in the text. Briefly, high p53 levels (0 and 0.25 ng/ml) slow down DNA replication by complex formation with POLι and idling () triggering HLTF- and ZRANB3- mediated fork remodeling at the highest p53 level (0 ng/ml). Low p53 levels (2.5 ng/ml) unleash fast DNA synthesis through TLS activities e.g. by POLι or POLη. At minimal p53 levels (4500 ng/ml) and reduced level of its target gene product POLη, PRIMPOL plays a key role in elongating DNA replication tracks. Such unrestrained repriming entails DNA replication stress and sensitizes cells to exogenous replication stress. An additional role of PRIMPOL in fork slow-down at high p53 levels (0 and 0.25 ng/ml) may involve repression of fast TLS such as initiated by POLη and/or gap formation promoting recombination-mediated template switch (). REV1 as TLS-POL loader, REV3L as TLS extender of TLS-POLs () and gap filler post-PRIMPOL (,) as well as HLTF promoting mono- and poly-ubiquitination of PCNA (,,,) are epistatic with multiple activities.

Publication

The levels of p53 govern the hierarchy of DNA damage tolerance pathway usage. (2024) Bryan A Castaño, et al. Nucleic Acids Res. 2024 Apr 24;52(7):3740-3760. Figure: F8. Homo sapiens

Disease mentions