scholarly journals Rev1 promotes replication through UV lesions in conjunction with DNA polymerases η, ι, and κ but not DNA polymerase ζ

2015 ◽  
Vol 29 (24) ◽  
pp. 2588-2602 ◽  
Author(s):  
Jung-Hoon Yoon ◽  
Jeseong Park ◽  
Juan Conde ◽  
Maki Wakamiya ◽  
Louise Prakash ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Crucial Role ◽  
Genome Stability ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Lesions ◽  
Human Cells ◽  
Uv Lesions ◽  
Human And Mouse

Translesion synthesis (TLS) DNA polymerases (Pols) promote replication through DNA lesions; however, little is known about the protein factors that affect their function in human cells. In yeast, Rev1 plays a noncatalytic role as an indispensable component of Polζ, and Polζ together with Rev1 mediates a highly mutagenic mode of TLS. However, how Rev1 functions in TLS and mutagenesis in human cells has remained unclear. Here we determined the role of Rev1 in TLS opposite UV lesions in human and mouse fibroblasts and showed that Rev1 is indispensable for TLS mediated by Polη, Polι, and Polκ but is not required for TLS by Polζ. In contrast to its role in mutagenic TLS in yeast, Rev1 promotes predominantly error-free TLS opposite UV lesions in humans. The identification of Rev1 as an indispensable scaffolding component for Polη, Polι, and Polκ, which function in TLS in highly specialized ways opposite a diverse array of DNA lesions and act in a predominantly error-free manner, implicates a crucial role for Rev1 in the maintenance of genome stability in humans.

scholarly journals A novel role of DNA polymerase λ in translesion synthesis in conjunction with DNA polymerase ζ

2021 ◽  
Vol 4 (4) ◽  
pp. e202000900
Author(s):  
Jung-Hoon Yoon ◽  
Debashree Basu ◽  
Karthi Sellamuthu ◽  
Robert E Johnson ◽  
Satya Prakash ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Dna Polymerase ◽  
Translesion Synthesis ◽  
Dna Lesions ◽  
Human Cells ◽  
Genome Integrity ◽  
Normal Cells ◽  
Normal Human ◽  
Dna Polymerase Λ

By extending synthesis opposite from a diverse array of DNA lesions, DNA polymerase (Pol) ζ performs a crucial role in translesion synthesis (TLS). In yeast and cancer cells, Rev1 functions as an indispensable scaffolding component of Polζ and it imposes highly error-prone TLS upon Polζ. However, for TLS that occurs during replication in normal human cells, Rev1 functions instead as a scaffolding component of Pols η, ι, and κ and Rev1-dependent TLS by these Pols operates in a predominantly error-free manner. The lack of Rev1 requirement for Polζ function in TLS in normal cells suggested that some other protein substitutes for this Rev1 role. Here, we identify a novel role of Polλ as an indispensable scaffolding component of Polζ. TLS studies opposite a number of DNA lesions support the conclusion that as an integral component, Polλ adapts Polζ-dependent TLS to operate in a predominantly error-free manner in human cells, essential for genome integrity and cellular homeostasis.

scholarly journals Role of Translesion Synthesis DNA Polymerases in DNA Replication in the Presence of a Weak DNA Polymerase δ in Saccharomyces cerevisiae

2018 ◽  
Vol 8 (2) ◽  
pp. 754-754
Author(s):  
Likui Zhang ◽  
Yanchao Huang ◽  
Xinyuan Zhu ◽  
Yuxiao Wang ◽  
Haoqiang Shi ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Replication ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Polymerase Δ

scholarly journals Role of Translesion Synthesis DNA Polymerases in DNA Replication in the Presence of a Weak DNA Polymerase δ in Saccharomyces cerevisiae

2017 ◽  
Vol 8 (2) ◽  
pp. 754-754
Author(s):  
Likui Zhang ◽  
Yanchao Huang ◽  
Xinyuan Zhu ◽  
Yuxiao Wang ◽  
Haoqiang Shi ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Replication ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Polymerase Δ

scholarly journals Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells

2016 ◽  
Vol 45 (3) ◽  
pp. 1270-1280 ◽  
Author(s):  
Leticia K. Lerner ◽  
Guilherme Francisco ◽  
Daniela T. Soltys ◽  
Clarissa R.R. Rocha ◽  
Annabel Quinet ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Translesion Synthesis ◽  
Human Cells ◽  
Predominant Role ◽  
Polymerase Eta ◽  
Dna Polymerase Eta

scholarly journals Human DNA Polymerase η Is Required for Common Fragile Site Stability during Unperturbed DNA Replication

2009 ◽  
Vol 29 (12) ◽  
pp. 3344-3354 ◽  
Author(s):  
Laurie Rey ◽  
Julia M. Sidorova ◽  
Nadine Puget ◽  
François Boudsocq ◽  
Denis S. F. Biard ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Polymerase ◽  
Genome Stability ◽  
Fragile Site ◽  
S Phase ◽  
Human Cells ◽  
Common Fragile Site ◽  
Exogenous Dna ◽  
Human Dna

ABSTRACT Human DNA polymerase η (Pol η) modulates susceptibility to skin cancer by promoting translesion DNA synthesis (TLS) past sunlight-induced cyclobutane pyrimidine dimers. Despite its well-established role in TLS synthesis, the role of Pol η in maintaining genome stability in the absence of external DNA damage has not been well explored. We show here that short hairpin RNA-mediated depletion of Pol η from undamaged human cells affects cell cycle progression and the rate of cell proliferation and results in increased spontaneous chromosome breaks and common fragile site expression with the activation of ATM-mediated DNA damage checkpoint signaling. These phenotypes were also observed in association with modified replication factory dynamics during S phase. In contrast to that seen in Pol η-depleted cells, none of these cellular or karyotypic defects were observed in cells depleted for Pol ι, the closest relative of Pol η. Our results identify a new role for Pol η in maintaining genomic stability during unperturbed S phase and challenge the idea that the sole functional role of Pol η in human cells is in TLS DNA damage tolerance and/or repair pathways following exogenous DNA damage.

scholarly journals Genetic evidence for reconfiguration of DNA polymerase θ active site for error-free translesion synthesis in human cells

2020 ◽  
Vol 295 (18) ◽  
pp. 5918-5927
Author(s):  
Jung-Hoon Yoon ◽  
Robert E. Johnson ◽  
Louise Prakash ◽  
Satya Prakash
Keyword(s):  
Dna Polymerase ◽  
Strong Evidence ◽  
Active Site ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Human Cells ◽  
New Paradigm ◽  
Tyrosine Residues ◽  
Action Mechanisms ◽  
Hoogsteen Base Pairing

The action mechanisms revealed by the biochemical and structural analyses of replicative and translesion synthesis (TLS) DNA polymerases (Pols) are retained in their cellular roles. In this regard, DNA polymerase θ differs from other Pols in that whereas purified Polθ misincorporates an A opposite 1,N6-ethenodeoxyadenosine (ϵdA) using an abasic-like mode, Polθ performs predominantly error-free TLS in human cells. To test the hypothesis that Polθ adopts a different mechanism for replicating through ϵdA in human cells than in the purified Pol, here we analyze the effects of mutations in the two highly conserved tyrosine residues, Tyr-2387 and Tyr-2391, in the Polθ active site. Our findings that these residues are indispensable for TLS by the purified Pol but are not required in human cells, as well as other findings, provide strong evidence that the Polθ active site is reconfigured in human cells to stabilize ϵdA in the syn conformation for Hoogsteen base pairing with the correct nucleotide. The evidence that a DNA polymerase can configure its active site entirely differently in human cells than in the purified Pol establishes a new paradigm for DNA polymerase function.

scholarly journals Site-specific proteolytic cleavage prevents ubiquitination and degradation of human REV3L, the catalytic subunit of DNA polymerase ζ

2020 ◽  
Vol 48 (7) ◽  
pp. 3619-3637 ◽  
Author(s):  
Fengting Wang ◽  
Pan Li ◽  
Yuan Shao ◽  
Yanyan Li ◽  
Kai Zhang ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Genome Stability ◽  
Catalytic Domain ◽  
Hct116 Cell ◽  
Point Mutations ◽  
Dna Lesions ◽  
Human Cells ◽  
Catalytic Subunit ◽  
New Paradigm ◽  
Site Specific

Abstract REV3L, the catalytic subunit of DNA polymerase ζ (Pol ζ), is indispensable for translesion DNA synthesis, which protects cells from deleterious DNA lesions resulting from various intrinsic and environmental sources. However, REV3L lacks a proofreading exonuclease activity and consequently bypasses DNA lesions at the expense of increased mutations, which poses a severe threat to genome stability. Here we report a site-specific proteolytic event of human REV3L. We show that REV3L is cleaved by a threonine aspartase, Taspase1 (TASP1), to generate an N-terminal 70-kDa fragment (N70) and a polypeptide carrying the C-terminal polymerase catalytic domain in human cells. Strikingly, such a post-translational cleavage event plays a vital role in controlling REV3L stability by preventing ubiquitination and proteasome-mediated degradation of REV3L. Indicative of the biological importance of the above REV3L post-translational processing, cellular responses to UV and cisplatin-induced DNA lesions are markedly impaired in human HCT116 cell derivatives bearing defined point mutations in the endogenous REV3L gene that compromise REV3L cleavage. These findings establish a new paradigm in modulating the abundance of REV3L through site-specific proteolysis in human cells.

Polymerization Past the N2-Isopropylguanine and the N6-Isopropyladenine DNA Lesions with the Translesion Synthesis DNA Polymerases η and ι and the Replicative DNA Polymerase α†

2005 ◽  
Vol 18 (9) ◽  
pp. 1451-1461 ◽  
Author(s):  
Fred W. Perrino ◽  
Scott Harvey ◽  
Patrick Blans ◽  
Stacy Gelhaus ◽  
William R. LaCourse ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Dna Polymerases ◽  
Translesion Synthesis ◽  
Dna Lesions ◽  
Dna Polymerase Α
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