Degradation of p12 Subunit by CRL4Cdt2 E3 Ligase Inhibits Fork Progression after DNA Damage

Abstract

Background:The mechanism for inhibiting fork progression after DNA damage still remains. Results: CRL4Cdt2 promotes the degradation of the p12. Cells expressing a stable form of p12 exhibit UV-resistant DNA synthesis and decreased inhibition of fork progression. Conclusion: p12 degradation by CRL4Cdt2 is critical for inhibiting fork progression. Significance: p12 degradation is one mechanism by which DNA damage in S-phase cells inhibits fork progression.

CDK1-dependent Inhibition of the E3 Ubiquitin Ligase CRL4CDT2 Ensures Robust Transition from S Phase to Mitosis

“…CDT1 is required in G 1 for rendering DNA replication origins competent for initiation in S phase (a process termed "origin licensing") (8,9). SET8 is the sole enzyme responsible for histone H4 lysine 20 monomethylation (H4K20me1) 4 and, like CDT1, is also required for origin licensing (10). Degradation of CDT1 and SET8 at the onset of S phase restricts DNA replication to no more than once per cell cycle by preventing relicensing of replicated origins.…”

“…Their destruction in S phase is particularly critical to ensure precise and efficient genome duplication (1)(2)(3)(4)(5)(6)(7). CDT1 is required in G 1 for rendering DNA replication origins competent for initiation in S phase (a process termed "origin licensing") (8,9).…”

“…Replication-coupled destruction is a particularly important protein control mechanism that coordinates the degradation of a cohort of proteins with the process of DNA synthesis. Much has been learned about how replication-coupled destruction is initiated in S phase (1)(2)(3)(4)(5), but less is known about how it is inhibited as S phase ends.…”

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

“…Two E3 ligases that target p12 for degradation have been identified: RNF8 [98] and CRL4 Cdt2 [61,77]. RNF8 was identified by a classical biochemical approach [98].…”

“…The p12 subunit of Pol δ possesses a PIP-degron, and is a substrate for CRL4 Cdt2 [61,77]. Mutation of the PIP-degron of p12 reduces its UV-induced degradation.…”