Characterization of human translesion DNA synthesis across a UV-induced DNA lesion

Hedglin, Mark; Pandey, Binod; Benkovic, Stephen J.

doi:10.7554/elife.19788

Cited by 37 publications

(86 citation statements)

References 50 publications

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“…4a) play key roles in TLS regulation (13, 145). Furthermore, post-translational modifications of PCNA and polymerases have been shown to influence cell cycle, replication fork movement, polymerase switch, and TLS activities (146, 147). Rev1 serves as a TLS hub and binds both TLS insertion polymerase (η, ι or κ) via RIR (Rev1 interacting region) (Fig.…”

Section: Regulation Of Tls and Sgrs Synthesismentioning

confidence: 99%

Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism

Yang

Gao

2018

Annu. Rev. Biochem.

190

182

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The number of DNA polymerases identified in each organism has mushroomed in last two decades. Most newly found DNA polymerases specialize in translesion synthesis and DNA repair instead of replication. Although intrinsic error rates are higher for translesion and repair polymerases than for replicative polymerases, the specialized polymerases increase genome stability and reduce tumorigenesis. Reflecting the numerous types of DNA lesions and variations of broken DNA ends, translesion and repair polymerases differ in structure, mechanism and function. Here we review the unique and general features of polymerases specialized in lesion-bypass, gap-filling and end-joining synthesis.

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Section: Regulation Of Tls and Sgrs Synthesismentioning

confidence: 99%

Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism

Yang

Gao

2018

Annu. Rev. Biochem.

190

182

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“…Pol δ alone has dramatically low, if any, affinity for P/T DNA and must anchor to PCNA to efficiently replicate the lagging strand templates 49, 51, 77, 109 . At a progressing replication fork, pol δ effectively captures a PCNA ring encircling a nascent P/T junction on the lagging strand and initiates DNA synthesis 77, 109–113 .…”

Section: When Two Worlds Collide: the Replisome Encountering A Uv-mentioning

confidence: 99%

“…At a progressing replication fork, pol δ effectively captures a PCNA ring encircling a nascent P/T junction on the lagging strand and initiates DNA synthesis 77, 109–113 . A pol δ holoenzyme inserts dNTPs at least 3 orders of magnitude faster than pol δ dissociates from PCNA encircling DNA 109, 113 .…”

Section: When Two Worlds Collide: the Replisome Encountering A Uv-mentioning

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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“…These studies described a widely accepted model of the function of ubiquitinated PCNA in TLS. However, a debate on the role of PCNA ubiquitination in TLS arose from recent extensive quantitative studies by Hedglin et al (8). Their results demonstrated that monoubiquitination of PCNA did not change the binding affinity between PCNA and pol, and the subsequent TLS across a DNA lesion was also independent of PCNA monoubiquitination.…”

mentioning

confidence: 99%

“…Their results demonstrated that monoubiquitination of PCNA did not change the binding affinity between PCNA and pol, and the subsequent TLS across a DNA lesion was also independent of PCNA monoubiquitination. They proposed that PCNA monoubiquitination indirectly promotes DNA synthesis by increasing the residence time of pol within the damaged sites, likely through altering the chromatin structure around damaged sites, although further studies are needed to test this hypothesis (8).…”

mentioning

confidence: 99%

The herpes simplex virus 1 UL36USP deubiquitinase suppresses DNA repair in host cells via deubiquitination of proliferating cell nuclear antigen

Dong

Guan

Chen

et al. 2017

Journal of Biological Chemistry

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Herpes simplex virus 1 (HSV-1) infection manipulates distinct host DNA-damage responses to facilitate virus proliferation, but the molecular mechanisms remain to be elucidated. One possible HSV-1 target might be DNA damage-tolerance mechanisms, such as the translesion synthesis (TLS) pathway. In TLS, proliferating cell nuclear antigen (PCNA) is monoubiquitinated in response to DNA damage-caused replication fork stalling. Ubiquitinated PCNA then facilitates the error-prone DNA polymerase η (polη)-mediated TLS, allowing the fork to bypass damaged sites. Because of the involvement of PCNA ubiquitination in DNA-damage repair, we hypothesized that the function of PCNA might be altered by HSV-1. Here we show that PCNA is a substrate of the HSV-1 deubiquitinase UL36USP, which has previously been shown to be involved mainly in virus uptake and maturation. In HSV-1-infected cells, viral infection-associated UL36USP consistently reduced PCNA ubiquitination. The deubiquitination of PCNA inhibited the formation of polη foci and also increased cell sensitivity to DNA-damage agents. Moreover, the catalytically inactive mutant UL36C40A failed to deubiquitinate PCNA. Of note, the levels of virus marker genes increased strikingly in cells infected with wild-type HSV-1, but only moderately in UL36C40A mutant virus-infected cells, indicating that the UL36USP deubiquitinating activity supports HSV-1 virus replication during infection. These findings suggest a role of UL36USP in the DNA damage-response pathway.

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Characterization of human translesion DNA synthesis across a UV-induced DNA lesion

Cited by 37 publications

References 50 publications

Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism

Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism

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

The herpes simplex virus 1 UL36USP deubiquitinase suppresses DNA repair in host cells via deubiquitination of proliferating cell nuclear antigen

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