REV1 promotes PCNA monoubiquitylation through interacting with ubiquitylated RAD18

Wang, Zhifeng; Huang, Min; Ma, Xinwen; Li, Huiming; Tang, Tie-Shan; Guo, Caixia

doi:10.1242/jcs.179408

Cited by 26 publications

(27 citation statements)

References 52 publications

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“…Furthermore, TLS polymerases themselves can influence the ubiquitination status of Rad18 and, as a consequence, ubiquitination of PCNA (Durando et al , 2013; Masuda et al , 2015). Very recently, Rev1 has been found to bind ubiquitinated Rad18 (Figure 3E, 4–5), leading to the release of the non-modified protomer from the dimer (Figure 3E, 5–6) and allowing it to ubiquitinate PCNA (Figure 3E, 2) (Wang et al , 2016). Furthermore, it has been proposed that pol η has the capacity to enhance and stabilize Rad18 (Figure 3E, 7).…”

Section: Tls Protein Interaction Networkmentioning

confidence: 99%

Translesion DNA polymerases in eukaryotes: what makes them tick?

Vaisman

Woodgate

2017

Critical Reviews in Biochemistry and Molecular Biology

224

204

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Life as we know it, simply would not exist without DNA replication. All living organisms utilize a complex machinery to duplicate their genomes and the central role in this machinery belongs to replicative DNA polymerases, enzymes that are specifically designed to copy DNA. “Hassle-free” DNA duplication exists only in an ideal world, while in real life, it is constantly threatened by a myriad of diverse challenges. Among the most pressing obstacles that replicative polymerases often cannot overcome by themselves, are lesions that distort the structure of DNA. Despite elaborate systems that cells utilize to cleanse their genomes of damaged DNA, repair is often incomplete. The persistence of DNA lesions obstructing the cellular replicases can have deleterious consequences. One of the mechanisms allowing cells to complete replication is “Translesion DNA Synthesis (TLS). TLS is intrinsically error-prone, but apparently, the potential downside of increased mutagenesis is a healthier outcome for the cell than incomplete replication. Although most of the currently identified eukaryotic DNA polymerases have been implicated in TLS, the best characterized are those belonging to the “Y-family” of DNA polymerases (pols η, ι, κ, and Rev1), which are thought to play major roles in the TLS of persisting DNA lesions in coordination with the B-family polymerase, pol ζ. In this review, we summarize the unique features of these DNA polymerases by mainly focusing on their biochemical and structural characteristics, as well as potential protein-protein interactions with other critical factors affecting TLS regulation.

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Section: Tls Protein Interaction Networkmentioning

confidence: 99%

Translesion DNA polymerases in eukaryotes: what makes them tick?

Vaisman

Woodgate

2017

Critical Reviews in Biochemistry and Molecular Biology

224

204

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“…RPA is critical for PCNA monoubiquitination as knockdown to undetectable levels in human and budding yeast cells effectively eliminates this PTM on DNA after treatment with replication-blocking agents (8,9). Additional cellular factors have also been implicated to various extents (4) and new discoveries continue to emerge (57,58). Some have been shown to bind Rad18 and/or PCNA and may promote PCNA monoubiquitination through direct interactions with these proteins.…”

Section: Rpa Enhances Monoubiquitination Of Pcna Encircling Stalled Pmentioning

confidence: 99%

Replication protein A dynamically regulates monoubiquitination of proliferating cell nuclear antigen

Hedglin

Aitha

Pedley

et al. 2019

Journal of Biological Chemistry

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Edited by Patrick SungDNA damage tolerance permits bypass of DNA lesions encountered during S-phase and may be carried out by translesion DNA synthesis (TLS). Human TLS requires selective monoubiquitination of proliferating cell nuclear antigen (PCNA) sliding clamps encircling damaged DNA. This posttranslational modification (PTM) is catalyzed by Rad6/Rad18. Recent studies revealed that replication protein A (RPA), the major ssDNA-binding protein, is involved in the regulation of PCNA monoubiquitination and interacts directly with Rad18 on chromatin and in the nucleoplasm. However, it is unclear how RPA regulates this critical PTM and what functional role(s) these interactions serve. Here, we developed an in vitro assay to quantitatively monitor PCNA monoubiquitination under in vivo scenarios. Results from extensive experiments revealed that RPA regulates Rad6/Rad18 activity in an ssDNA-dependent manner. We found that "DNA-free" RPA inhibits monoubiquitination of free PCNA by directly interacting with Rad18. This interaction is promoted under native conditions when there is an overabundance of free RPA in the nucleoplasm where Rad6/ Rad18 and a significant fraction of PCNA reside. During DNA replication stress, RPA binds the ssDNA exposed downstream of stalled primer/template (P/T) junctions, releasing Rad6/ Rad18. RPA restricted the resident PCNAs to the upstream duplex regions by physically blocking diffusion of PCNA along ssDNA, and this activity was required for efficient monoubiquitination of PCNA on DNA. Furthermore, upon binding ssDNA, RPA underwent a conformational change that increased its affinity for Rad18. Rad6/Rad18 complexed with ssDNA-bound RPA was active, and this interaction may selectively promote monoubiquitination of PCNA on long RPAcoated ssDNA.

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“…The protein levels, self-association, and cellular localization of RAD18 are regulated via its mono-and polyubiquitination, which control the overall activity of RAD18 in mammalian cells (Miyase et al 2005;Zeman et al 2014;Zlatanou et al 2016). REV1 preferentially binds to monoubiquitinated RAD18 via its ubiquitin-binding motifs (UBMs) (Wang et al 2016). This binding could modulate the ubiquitination-mediated regulatory network of RAD18, leading to the subsequent stimulation of PCNA monoubiquitination (Wang et al 2016).…”

Section: Regulation Of Pcna Ubiquitinationmentioning

confidence: 99%

Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways

Masuda

Masutani

2019

Critical Reviews in Biochemistry and Molecular Biology

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DNA is constantly exposed to a wide variety of exogenous and endogenous agents, and most DNA lesions inhibit DNA synthesis. To cope with such problems during replication, cells have molecular mechanisms to resume DNA synthesis in the presence of DNA lesions, which are known as DNA damage tolerance (DDT) pathways. The concept of ubiquitination-mediated regulation of DDT pathways in eukaryotes was established via genetic studies in the yeast Saccharomyces cerevisiae, in which two branches of the DDT pathway are regulated via ubiquitination of proliferating cell nuclear antigen (PCNA): translesion DNA synthesis (TLS) and homology-dependent repair (HDR), which are stimulated by mono-and polyubiquitination of PCNA, respectively. Over the subsequent nearly two decades, significant progress has been made in understanding the mechanisms that regulate DDT pathways in other eukaryotes. Importantly, TLS is intrinsically error-prone because of the miscoding nature of most damaged nucleotides and inaccurate replication of undamaged templates by TLS polymerases (pols), whereas HDR is theoretically error-free because the DNA synthesis is thought to be predominantly performed by pol d, an accurate replicative DNA pol, using the undamaged sister chromatid as its template. Thus, the regulation of the choice between the TLS and HDR pathways is critical to determine the appropriate biological outcomes caused by DNA damage. In this review, we summarize our current understanding of the species-specific regulatory mechanisms of PCNA ubiquitination and how cells choose between TLS and HDR. We then provide a hypothetical model for the spatiotemporal regulation of DDT pathways in human cells.

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REV1 promotes PCNA monoubiquitylation through interacting with ubiquitylated RAD18

Cited by 26 publications

References 52 publications

Translesion DNA polymerases in eukaryotes: what makes them tick?

Translesion DNA polymerases in eukaryotes: what makes them tick?

Replication protein A dynamically regulates monoubiquitination of proliferating cell nuclear antigen

Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways

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