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 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 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

Chemotherapy in malignant disease

1970 ◽  
Vol 8 (4) ◽  
pp. 13-16
Keyword(s):  
Cancer Cells ◽  
Cancer Chemotherapy ◽  
Anticancer Agents ◽  
Antimicrobial Chemotherapy ◽  
Malignant Disease ◽  
Human Cells ◽  
Normal Cells ◽  
Different Types ◽  
Normal Human ◽  
Normal Human Cells

Cancer chemotherapy, unlike antimicrobial chemotherapy, is not based on absolute metabolic differences between cancer cells and normal human cells. Anticancer agents inhibit the growth of cells, whether normal or malignant, though different types of cell vary in their susceptibility to these agents, and in their capacity for recovery. The usefulness of these drugs is thus limited by their effects on normal cells.

scholarly journals The wages of CIN

2008 ◽  
Vol 180 (4) ◽  
pp. 661-663 ◽  
Author(s):  
Karen W. Yuen ◽  
Arshad Desai
Keyword(s):  
Cancer Cells ◽  
Solid Tumors ◽  
Chromosomal Instability ◽  
Chromosome Instability ◽  
Spindle Checkpoint ◽  
Human Cells ◽  
Normal Cells ◽  
Chromosome Missegregation ◽  
Cell Biol ◽  
The Relationship

Aneuploidy and chromosome instability (CIN) are hallmarks of the majority of solid tumors, but the relationship between them is not well understood. In this issue, Thompson and Compton (Thompson, S.L., and D.A. Compton. 2008. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell. Biol. 180:665–672) investigate the mechanism of CIN in cancer cells and find that CIN arises primarily from defective kinetochore–spindle attachments that evade detection by the spindle checkpoint and persist into anaphase. They also explore the consequences of artificially elevating chromosome missegregation in otherwise karyotypically normal cells. Their finding that induced aneuploidy is rapidly selected against suggests that the persistence of aneuploid cells in tumors requires not only chromosome missegregation but also additional, as yet poorly defined events.

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 The Functional Role of MnSOD as a Biomarker of Human Diseases and Therapeutic Potential of a New Isoform of a Human Recombinant MnSOD

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Antonella Borrelli ◽  
Antonietta Schiattarella ◽  
Patrizia Bonelli ◽  
Franca Maria Tuccillo ◽  
Franco Maria Buonaguro ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Manganese Superoxide Dismutase ◽  
Therapeutic Potential ◽  
Human Diseases ◽  
Leader Peptide ◽  
X Rays ◽  
Normal Cells ◽  
Initial Application ◽  
Prevention Of Cancer

Reactive oxygen species (ROS) are generated as a consequence of metabolic reactions in the mitochondria of eukaryotic cells. This work describes the role of the manganese superoxide dismutase (MnSOD) as a biomarker of different human diseases and proposes a new therapeutic application for the prevention of cancer and its treatment. The paper also describes how a new form of human MnSOD was discovered, its initial application, and its clinical potentials. The MnSOD isolated from a human liposarcoma cell line (LSA) was able to kill cancer cells expressing estrogen receptors, but it did not have cytotoxic effects on normal cells. Together with its oncotoxic activity, the recombinant MnSOD (rMnSOD) exerts a radioprotective effect on normal cells irradiated with X-rays. The rMnSOD is characterized by the presence of a leader peptide, which allows the protein to enter cells: this unique property can be used in the radiodiagnosis of cancer or chemotherapy, conjugating radioactive substances or chemotherapic drugs to the leader peptide of the MnSOD. Compared to traditional chemotherapic agents, the drugs conjugated with the leader peptide of MnSOD can selectively reach and enter cancer cells, thus reducing the side effects of traditional treatments.

scholarly journals Arginine Methylation Regulates Telomere Length and Stability

2009 ◽  
Vol 29 (18) ◽  
pp. 4918-4934 ◽  
Author(s):  
Taylor R. H. Mitchell ◽  
Kimberly Glenfield ◽  
Kajaparan Jeyanthan ◽  
Xu-Dong Zhu
Keyword(s):  
Cell Proliferation ◽  
Cancer Cells ◽  
Telomere Length ◽  
Control Cell ◽  
Arginine Methylation ◽  
Human Cells ◽  
Focus Formation ◽  
Basic Domain ◽  
Normal Human ◽  
Normal Human Cells

ABSTRACT TRF2, a component of the shelterin complex, functions to protect telomeres. TRF2 contains an N-terminal basic domain rich in glycines and arginines, similar to the GAR motif that is methylated by protein arginine methyltransferases. However, whether arginine methylation regulates TRF2 function has not been determined. Here we report that amino acid substitutions of arginines with lysines in the basic domain of TRF2 induce telomere dysfunction-induced focus formation, leading to induction of cellular senescence. We have demonstrated that cells overexpressing TRF2 lysine mutants accumulate telomere doublets, indicative of telomere instability. We uncovered that TRF2 interacts with PRMT1, and its arginines in the basic domain undergo PRMT1-mediated methylation both in vitro and in vivo. We have shown that loss of PRMT1 induces growth arrest in normal human cells but has no effect on cell proliferation in cancer cells, suggesting that PRMT1 may control cell proliferation in a cell type-specific manner. We found that depletion of PRMT1 in normal human cells results in accumulation of telomere doublets, indistinguishable from overexpression of TRF2 lysine mutants. PRMT1 knockdown in cancer cells upregulates TRF2 association with telomeres, promoting telomere shortening. Taken together, these results suggest that PRMT1 may control telomere length and stability in part through TRF2 methylation.

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