Ubiquitin mediates the physical and functional interaction between human DNA polymerases η and ι

McIntyre, Justyna; Vidal, Antonio E.; McLenigan, Mary P.; Bomar, Martha G.; Curti, Elena; McDonald, John P.; Plosky, Brian S.; Ohashi, Eiji; Woodgate, Roger

doi:10.1093/nar/gks1277

Cited by 23 publications

(29 citation statements)

References 42 publications

(84 reference statements)

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“…Following UV irradiation of human cells, pols η, ζ, κ, and ι, accumulate into replication foci on damaged DN A 34, 196 . In particular, Rad6/Rad18 may physically deliver pol η●pol ι complexes to UV-irradiated DNA in a process driven by damaged-induced PTMs to the involved proteins 34, 245–247 . Furthermore, UV irradiation elicits monoubiquitination of PCNA by Rad6/Rad18 and phosphorylation of pol η, both of which are imperative for pol η-mediated TLS in vivo 34, 198 .…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands: Unique Detours around the Same Obstacle

Hedglin

Benkovic

2017

Chem. Rev.

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During S-phase, minor DNA damage may be overcome by DNA damage tolerance (DDT) pathways that bypass such obstacles, postponing repair of the offending damage to complete the cell cycle and maintain cell survival. In translesion DNA synthesis (TLS), specialized DNA polymerases replicate the damaged DNA, allowing stringent DNA synthesis by a replicative polymerase to resume beyond the offending damage. Dysregulation of this DDT pathway in human cells leads to increased mutations rates that may contribute to the onset of cancer. Furthermore, TLS affords human cancer cells the ability to counteract chemotherapeutic agents that elicit cell death by damaging DNA in actively replicating cells. Currently, it is unclear how this critical pathway unfolds, in particular where and when TLS occurs on each template strand. Given the semi-discontinuous nature of DNA replication, it is likely that TLS on the leading and lagging strand templates is unique for each strand. Since the discovery of DDT in the late 1960’s, most studies on TLS in eukaryotes have focused on DNA lesions resulting from ultraviolet (UV) radiation exposure. In this review, we re-visit these and other related studies to dissect the step-by-step intricacies of this complex process, provide our current understanding of TLS on leading and lagging strand templates, and propose testable hypotheses to gain further insights.

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Section: Discussionmentioning

confidence: 99%

Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands: Unique Detours around the Same Obstacle

Hedglin

Benkovic

2017

Chem. Rev.

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“…It has been reported that a ubiquitin-binding zinc finger (UBZ) domain near the C terminus of Polƞ is responsible for an interaction with monoubiquitinated PCNA [31,32], which differs from Rev1 with two UBM domains [20], making it possible to create Ub point mutations that differentially affect its interaction with UBZ (Polg) and UBM (Rev1). The Ub-I44 residue has been reported to be critical for binding Polg [33]. Indeed, the PCNA-Ub (I44A) mutation barely affected its interaction with GFP-Rev1 ( Fig.…”

Section: Selection Of Ub Amino Acid Substitutions Differentially Affementioning

confidence: 94%

Rev1 plays central roles in mammalian DNA‐damage tolerance in response to UV irradiation

Niu

Chen

et al. 2019

The FEBS Journal

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Rev1, a Y‐family DNA polymerase, is involved in the tolerance of DNA damage by translesion DNA synthesis (TLS). Previous studies have shown that the C‐terminal domain (CTD) and ubiquitin (Ub)‐binding (UBM) domains of Rev1 play important roles in UV‐damage tolerance, but how these domains contribute to the process remains unclear. In this study, we created Ub mutations in a proliferating cell nuclear antigen (PCNA)‐Ub fusion that differentially affect its interaction with Rev1 and Polη and found that UV‐damage tolerance depends on its interaction with Rev1 but not Polη. We also created Rev1‐UBM mutations altering its interaction with a PCNA‐Ub fusion and Rev1‐CTD mutations affecting its interaction with Polη and the Rev7 subunit of Polζ. We thus demonstrated that elevated expression of Rev1 alone is sufficient to confer enhanced UV‐damage tolerance and that this tolerance depends on its physical interaction with monoubiquitinated PCNA and Polζ but is independent of Polη. Collectively, these studies reveal central roles played by Rev1 in coordinating UV‐damage response pathway choice in mammalian cells.

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“…Therefore, pol η de-ubiquitination in cells exposed to DNA damaging agents is required for the efficient interaction with the Ub-PCNA and subsequent recruitment to the site of replication (Bienko et al , 2005; Bienko et al , 2010; Plosky et al , 2006). On the other hand, mono-ubiquitination of either pol η or pol ι enhances the interaction between the two polymerases (Figure 3A), which it thought to occur through their respective UBZ and UBM ubiquitin-binding domains (McIntyre et al , 2013). Since the interaction with pol η facilitates the localization of pol ι into replication factories (Kannouche and Stary, 2003), it is possible that the ubiquitination of polι is dictated by the need to retain it in the vicinity of pol η.…”

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

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203

197

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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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Ubiquitin mediates the physical and functional interaction between human DNA polymerases η and ι

Cited by 23 publications

References 42 publications

Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands: Unique Detours around the Same Obstacle

Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands: Unique Detours around the Same Obstacle

Rev1 plays central roles in mammalian DNA‐damage tolerance in response to UV irradiation

Translesion DNA polymerases in eukaryotes: what makes them tick?

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