Abstract
The level of monoubiquitinated proliferating cell nuclear antigen (PCNA) is closely linked with DNA damage bypass to protect cells from a high level of mutagenesis. However, it remains unclear how the level of monoubiquitinated PCNA is regulated. Here, we demonstrate that human ELG1 protein, which comprises an alternative replication factor C (RFC) complex and plays an important role in preserving genomic stability, as an interacting partner for the USP1 (ubiquitin-specific protease 1)-UAF1 (USP1-associated factor 1) complex, a deubiquitinating enzyme complex for PCNA and FANCD2. ELG1 protein interacts with PCNAs that are localized at stalled replication forks. ELG1 knockdown specifically resulted in an increase in the level of PCNA monoubiquitination without affecting the level of FANCD2 ubiquitination. It is a novel function of ELG1 distinct from its role as an alternative RFC complex because knockdowns of any other RFC subunits or other alternative RFCs did not affect PCNA monoubiquitination. Lastly, we identified a highly conserved N-terminal domain in ELG1 that was responsible for the USP1-UAF1 interaction as well as the activity to down-regulate PCNA monoubiquitination. Taken together, ELG1 specifically directs USP1-UAF1 complex for PCNA deubiquitination.
Highlights
Proliferating cell nuclear antigen (PCNA)4 functions in DNA replication, repair, and recombination as a sliding clamp for various DNA replication polymerases and a scaffold for many DNA repair and recombination enzymes [1]
Because ELG1 interacts with the USP1-UAF1 complex and the yeast Elg1p protein interacts with PCNA [24], we examined whether human ELG1 could interact with human PCNA
Precise regulation of PCNA ubiquitination is important for translesion synthesis (TLS) pathway of postreplication repair as well as suppressing the mutagenic effects of TLS pathway in unperturbed cells [6, 7, 9]
Summary
Proliferating cell nuclear antigen (PCNA)4 functions in DNA replication, repair, and recombination as a sliding clamp for various DNA replication polymerases and a scaffold for many DNA repair and recombination enzymes [1]. We identified a highly conserved N-terminal domain in ELG1 that was responsible for the USP1-UAF1 interaction as well as the activity to down-regulate PCNA monoubiquitination. We identified human ELG1 as an interacting protein of the USP1-UAF1 complex. The interaction of ELG1 with PCNA and the USP1-UAF1 complex
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