Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability

Nayak, Sumeet; Calvo, Jennifer A.; Cantor, Sharon B.

doi:10.1080/14728222.2021.1864321

Cited by 20 publications

(11 citation statements)

References 154 publications

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“…Many of these mechanisms offer potential targets for future chemotherapeutics. In particular, the role of TLS in both chemoresistance and mutagenesis has made TLS inhibitors a potentially promising future anti-cancer tool ( Nayak et al, 2021 ). Further advances in biochemistry and structural biology will be key to fully understanding the mechanisms for maintaining replisome progression and how these can be exploited for disease treatment.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms for Maintaining Eukaryotic Replisome Progression in the Presence of DNA Damage

Guilliam

2021

Front. Mol. Biosci.

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The eukaryotic replisome coordinates template unwinding and nascent-strand synthesis to drive DNA replication fork progression and complete efficient genome duplication. During its advancement along the parental template, each replisome may encounter an array of obstacles including damaged and structured DNA that impede its progression and threaten genome stability. A number of mechanisms exist to permit replisomes to overcome such obstacles, maintain their progression, and prevent fork collapse. A combination of recent advances in structural, biochemical, and single-molecule approaches have illuminated the architecture of the replisome during unperturbed replication, rationalised the impact of impediments to fork progression, and enhanced our understanding of DNA damage tolerance mechanisms and their regulation. This review focusses on these studies to provide an updated overview of the mechanisms that support replisomes to maintain their progression on an imperfect template.

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Section: Discussionmentioning

confidence: 99%

Mechanisms for Maintaining Eukaryotic Replisome Progression in the Presence of DNA Damage

Guilliam

2021

Front. Mol. Biosci.

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“…Here, we showed, that alternative p53isoforms, Δ133p53α and Δ160p53α, in particular, interfere with coexpressed p53α in DDT. Since homology-directed DDT-pathways, involving HLTF-and ZRANB3-mediated fork reversal, protect the genome from unrestrained and mutagenic bypass mechanisms like TLS [65,66], we anticipate that these isoforms increase genomic instability. Besides, the same ΔN-isoforms stimulate proliferation and inhibit apoptosis [15,23], all-in-all creating a dangerous combination of pro-mutagenic and pro-survival features, known to drive carcinogenesis.…”

Section: Alternative P53-isoforms Show Loss-of-function In the P53-polι-dependent Ddt-pathway Mediating Homology-directed Bypass Of Replimentioning

confidence: 99%

p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway

et al. 2021

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The recently discovered p53-dependent DNA damage tolerance (DDT) pathway relies on its biochemical activities in DNA-binding, oligomerization, as well as complex formation with the translesion synthesis (TLS) polymerase iota (POLι). These p53-POLι complexes slow down nascent DNA synthesis for safe, homology-directed bypass of DNA replication barriers. In this study, we demonstrate that the alternative p53-isoforms p53β, p53γ, Δ40p53α, Δ133p53α, and Δ160p53α differentially affect this p53-POLι-dependent DDT pathway originally described for canonical p53α. We show that the C-terminal isoforms p53β and p53γ, comprising a truncated oligomerization domain (OD), bind PCNA. Conversely, N-terminally truncated isoforms have a reduced capacity to engage in this interaction. Regardless of the specific loss of biochemical activities required for this DDT pathway, all alternative isoforms were impaired in promoting POLι recruitment to PCNA in the chromatin and in decelerating DNA replication under conditions of enforced replication stress after Mitomycin C (MMC) treatment. Consistent with this, all alternative p53-isoforms no longer stimulated recombination, i.e., bypass of endogenous replication barriers. Different from the other isoforms, Δ133p53α and Δ160p53α caused a severe DNA replication problem, namely fork stalling even in untreated cells. Co-expression of each alternative p53-isoform together with p53α exacerbated the DDT pathway defects, unveiling impaired POLι recruitment and replication deceleration already under unperturbed conditions. Such an inhibitory effect on p53α was particularly pronounced in cells co-expressing Δ133p53α or Δ160p53α. Notably, this effect became evident after the expression of the isoforms in tumor cells, as well as after the knockdown of endogenous isoforms in human hematopoietic stem and progenitor cells. In summary, mimicking the situation found to be associated with many cancer types and stem cells, i.e., co-expression of alternative p53-isoforms with p53α, carved out interference with p53α functions in the p53-POLι-dependent DDT pathway.

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“…Therefore, TLS increases the mutation rate and the risk of tumorigenesis while maintaining genomic integrity [ 6 , 7 ]. In addition, as an important part of the DNA damage tolerance pathways, TLS protects tumor cells and allows them to overcome oncogene-induced replication stress (OIRS) during tumor progression [ 8 , 9 ]. Taken together, these observations indicate that TLS is closely related to carcinogenesis and tumor progression.…”

Section: Introductionmentioning

confidence: 99%

REV1 promotes lung tumorigenesis by activating the Rad18/SERTAD2 axis

et al. 2022

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REV1 is the central member of the family of TLS polymerases, which participate in various DNA damage repair and tolerance pathways and play a significant role in maintaining genomic stability. However, the role of REV1 in tumors is rarely reported. In this study, we found that the expression of REV1 was significantly upregulated in lung cancer tissues compared with matched adjacent tissues and was associated with poor prognosis. Functional experiments demonstrated that REV1 silencing decreased the growth and proliferation capacity of lung cancer cells. Mechanistically, REV1 upregulated the expression of SERTAD2 in a Rad18-dependent manner, thereby promoting lung carcinogenesis. A novel REV1 inhibitor, JH-RE-06, suppressed lung tumorigenesis in vivo and in vitro and was shown to be safe and well tolerated. Our study confirmed that REV1 is a potential diagnostic marker and therapeutic target for lung cancer and that JH-RE-06 may be a safe and efficient therapeutic agent for NSCLC.

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Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability

Cited by 20 publications

References 154 publications

Mechanisms for Maintaining Eukaryotic Replisome Progression in the Presence of DNA Damage

Mechanisms for Maintaining Eukaryotic Replisome Progression in the Presence of DNA Damage

p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway

REV1 promotes lung tumorigenesis by activating the Rad18/SERTAD2 axis

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