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Article ; Online: UV light-induced dual promoter mutations dismantle the telomeric guardrails in melanoma.

Sanford, Samantha L / Opresko, Patricia L

2022 Volume 122, Page(s) 103446

Abstract: Understanding how benign nevi can progress to invasive and metastatic Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, USAelanoma is critical for developing interventions and therapeutics for this ... ...

Abstract	Understanding how benign nevi can progress to invasive and metastatic Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, USAelanoma is critical for developing interventions and therapeutics for this most deadly form of skin cancer. UV-induced mutations in the telomerase TERT gene promoter occur in the majority of melanomas but fail to prevent telomere shortening despite telomerase upregulation. This suggests additional "hits" are required to enable telomere maintenance. A new study in Science identified somatic variants in the promoter of the gene that encodes telomere shelterin protein TPP1 in human melanomas. These variants show mutational signatures of UV-induced DNA damage and upregulate TPP1 expression, which synergizes with telomerase to lengthen telomeres. This study provides evidence that TPP1 promoter variants are a critical second hit to prevent telomere shortening and promote immortalization of melanoma cells.
MeSH term(s)	Humans ; Telomerase/genetics ; Telomerase/metabolism ; Ultraviolet Rays/adverse effects ; Telomere/metabolism ; Telomere-Binding Proteins/genetics ; Telomere-Binding Proteins/metabolism ; Melanoma/genetics ; Mutation
Chemical Substances	Telomerase (EC 2.7.7.49) ; Telomere-Binding Proteins
Language	English
Publishing date	2022-12-30
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2022.103446
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Article: Translating the telomeres.

De Rosa, Mariarosaria / Opresko, Patricia L

Trends in genetics : TIG

2023 Volume 39, Issue 8, Page(s) 593–595

Abstract: Telomeres are transcribed into long noncoding telomeric repeat-containing RNA (TERRA). Or so we thought. Recently, Al-Turki and Griffith provided evidence that TERRA can code for valine-arginine (VR) or glycine-leucine (GL) dipeptide repeat proteins by ... ...

Abstract	Telomeres are transcribed into long noncoding telomeric repeat-containing RNA (TERRA). Or so we thought. Recently, Al-Turki and Griffith provided evidence that TERRA can code for valine-arginine (VR) or glycine-leucine (GL) dipeptide repeat proteins by undergoing repeat-associated non-ATG (RAN) translation. This finding uncovers a new mechanism by which telomeres can impact cellular function.
MeSH term(s)	RNA, Long Noncoding/genetics ; Telomere/genetics ; Telomere/metabolism
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2023-05-12
Publishing country	England
Document type	Journal Article
ZDB-ID	619240-3
ISSN	1362-4555 ; 0168-9525 ; 0168-9479
ISSN (online)	1362-4555
ISSN	0168-9525 ; 0168-9479
DOI	10.1016/j.tig.2023.04.009
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Article ; Online: Telomere Fragility and MiDAS: Managing the Gaps at the End of the Road.

Barnes, Ryan P / Thosar, Sanjana A / Opresko, Patricia L

Genes

2023 Volume 14, Issue 2

Abstract: Telomeres present inherent difficulties to the DNA replication machinery due to their repetitive sequence content, formation of non-B DNA secondary structures, and the presence of the nucleo-protein t-loop. Especially in cancer cells, telomeres are hot ... ...

Abstract	Telomeres present inherent difficulties to the DNA replication machinery due to their repetitive sequence content, formation of non-B DNA secondary structures, and the presence of the nucleo-protein t-loop. Especially in cancer cells, telomeres are hot spots for replication stress, which can result in a visible phenotype in metaphase cells termed "telomere fragility". A mechanism cells employ to mitigate replication stress, including at telomeres, is DNA synthesis in mitosis (MiDAS). While these phenomena are both observed in mitotic cells, the relationship between them is poorly understood; however, a common link is DNA replication stress. In this review, we will summarize what is known to regulate telomere fragility and telomere MiDAS, paying special attention to the proteins which play a role in these telomere phenotypes.
MeSH term(s)	DNA Replication ; DNA/metabolism ; Mitosis ; Phenotype ; Telomere/metabolism
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2023-01-29
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14020348
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Article: OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence.

De Rosa, Mariarosaria / Barnes, Ryan P / Nyalapatla, Prasanth R / Wipf, Peter / Opresko, Patricia L

bioRxiv : the preprint server for biology

2023

Abstract: Telomeres are prone to formation of the common oxidative lesion 8-oxoguanine (8oxoG), and the acute production of 8oxoG damage at telomeres is sufficient to drive rapid cellular senescence. OGG1 and MUTYH glycosylases initiate base excision repair (BER) ... ...

Abstract	Telomeres are prone to formation of the common oxidative lesion 8-oxoguanine (8oxoG), and the acute production of 8oxoG damage at telomeres is sufficient to drive rapid cellular senescence. OGG1 and MUTYH glycosylases initiate base excision repair (BER) at 8oxoG sites to remove the lesion or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced senescence, and loss of both glycosylases results in a near complete rescue. Loss of these glycosylases also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that single-stranded break (SSB) intermediates arising downstream of glycosylase activity impair telomere replication. The failure to initiate BER in glycosylase-deficient cells suppresses PARylation at SSB intermediates and confers resistance to the synergistic effects of PARP inhibitors on damage-induced senescence. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which impair telomere replication and stability.
Language	English
Publishing date	2023-04-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.10.536247
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Article ; Online: Oxidative guanine base damage plays a dual role in regulating productive ALT-associated homology-directed repair.

Thosar, Sanjana A / Barnes, Ryan P / Detwiler, Ariana / Bhargava, Ragini / Wondisford, Anne / O'Sullivan, Roderick J / Opresko, Patricia L

Cell reports

2024 Volume 43, Issue 1, Page(s) 113656

Abstract: Cancer cells maintain telomeres by upregulating telomerase or alternative lengthening of telomeres (ALT) via homology-directed repair at telomeric DNA breaks. 8-Oxoguanine (8oxoG) is a highly prevalent endogenous DNA lesion in telomeric sequences, ... ...

Abstract	Cancer cells maintain telomeres by upregulating telomerase or alternative lengthening of telomeres (ALT) via homology-directed repair at telomeric DNA breaks. 8-Oxoguanine (8oxoG) is a highly prevalent endogenous DNA lesion in telomeric sequences, altering telomere structure and telomerase activity, but its impact on ALT is unclear. Here, we demonstrate that targeted 8oxoG formation at telomeres stimulates ALT activity and homologous recombination specifically in ALT cancer cells. Mechanistically, an acute 8oxoG induction increases replication stress, as evidenced by increased telomere fragility and ATR kinase activation at ALT telomeres. Furthermore, ALT cells are more sensitive to chronic telomeric 8oxoG damage than telomerase-positive cancer cells, consistent with increased 8oxoG-induced replication stress. However, telomeric 8oxoG production in G2 phase, when ALT telomere elongation occurs, impairs telomeric DNA synthesis. Our study demonstrates that a common oxidative base lesion has a dual role in regulating ALT depending on when the damage arises in the cell cycle.
MeSH term(s)	Telomerase/metabolism ; Telomere Homeostasis ; Telomere/metabolism ; Oxidative Stress ; Guanine
Chemical Substances	Telomerase (EC 2.7.7.49) ; Guanine (5Z93L87A1R)
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.113656
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Article ; Online: Targeted Formation of 8-Oxoguanine in Telomeres.

Barnes, Ryan P / Thosar, Sanjana A / Fouquerel, Elise / Opresko, Patricia L

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2444, Page(s) 141–159

Abstract: Mammalian telomeres are guanine-rich sequences which cap the ends of linear chromosomes. While recognized as sites sensitive to oxidative stress, studies on the consequences of oxidative damage to telomeres have been primarily limited to experimental ... ...

Abstract	Mammalian telomeres are guanine-rich sequences which cap the ends of linear chromosomes. While recognized as sites sensitive to oxidative stress, studies on the consequences of oxidative damage to telomeres have been primarily limited to experimental conditions which cause oxidative damage throughout the whole genome and cell. We developed a chemoptogenetic tool (FAP-mCER-TRF1) to specifically induce singlet oxygen at telomeres, resulting in the formation of the common oxidative lesion 8-oxo-guanine. Here, we describe this tool and detail how to generate cell lines which express FAP-mCER-TRF1 at telomeres and verify the formation of 8-oxo-guanine.
MeSH term(s)	Animals ; DNA Damage ; Guanine/analogs & derivatives ; Guanine/metabolism ; Mammals/genetics ; Oxidative Stress/genetics ; Telomere/genetics ; Telomere/metabolism
Chemical Substances	8-hydroxyguanine (5614-64-2) ; Guanine (5Z93L87A1R)
Language	English
Publishing date	2022-03-14
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2063-2_9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Vectorial folding of telomere overhang promotes higher accessibility.

Paul, Tapas / Opresko, Patricia L / Ha, Taekjip / Myong, Sua

Nucleic acids research

2022 Volume 50, Issue 11, Page(s) 6271–6283

Abstract: Human telomere overhang composed of tandem repeats of TTAGGG folds into G-quadruplex (G4). Unlike in an experimental setting in the test tube in which the entire length is allowed to fold at once, inside the cell, the overhang is expected to fold as it ... ...

Abstract	Human telomere overhang composed of tandem repeats of TTAGGG folds into G-quadruplex (G4). Unlike in an experimental setting in the test tube in which the entire length is allowed to fold at once, inside the cell, the overhang is expected to fold as it is synthesized directionally (5' to 3') and released segmentally by a specialized enzyme, the telomerase. To mimic such vectorial G4 folding process, we employed a superhelicase, Rep-X which can unwind DNA to release the TTAGGG repeats in 5' to 3' direction. We demonstrate that the folded conformation achieved by the refolding of full sequence is significantly different from that of the vectorial folding for two to eight TTAGGG repeats. Strikingly, the vectorially folded state leads to a remarkably higher accessibility to complementary C-rich strand and the telomere binding protein POT1, reflecting a less stably folded state resulting from the vectorial folding. Importantly, our study points to an inherent difference between the co-polymerizing and post-polymerized folding of telomere overhang that can impact telomere architecture and downstream processes.
MeSH term(s)	DNA/chemistry ; G-Quadruplexes ; Humans ; Nucleic Acid Conformation ; Shelterin Complex ; Telomerase/metabolism ; Telomere/chemistry ; Telomere/genetics ; Telomere-Binding Proteins/metabolism
Chemical Substances	POT1 protein, human ; Shelterin Complex ; Telomere-Binding Proteins ; DNA (9007-49-2) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2022-06-10
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkac401
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Article: Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress.

De Rosa, Mariarosaria / Johnson, Samuel A / Opresko, Patricia L

Frontiers in cell and developmental biology

2021 Volume 9, Page(s) 758402

Abstract: Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can ... ...

Abstract	Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can contribute to either cellular senescence and aging, or tumorigenesis. Human reproductive cells, some stem cells, and most cancer cells, express the enzyme telomerase to restore telomeric DNA. Numerous studies have shown that oxidative stress caused by excess reactive oxygen species is associated with accelerated telomere shortening and dysfunction. Telomeric repeat sequences are remarkably susceptible to oxidative damage and are preferred sites for the production of the mutagenic base lesion 8-oxoguanine, which can alter telomere length homeostasis and integrity. Therefore, knowledge of the repair pathways involved in the processing of 8-oxoguanine at telomeres is important for advancing understanding of the pathogenesis of degenerative diseases and cancer associated with telomere instability. The highly conserved guanine oxidation (GO) system involves three specialized enzymes that initiate distinct pathways to specifically mitigate the adverse effects of 8-oxoguanine. Here we introduce the GO system and review the studies focused on investigating how telomeric 8-oxoguanine processing affects telomere integrity and overall genome stability. We also discuss newly developed technologies that target oxidative damage selectively to telomeres to investigate roles for the GO system in telomere stability.
Language	English
Publishing date	2021-11-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.758402
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Article ; Online: How DNA damage and non-canonical nucleotides alter the telomerase catalytic cycle.

Sanford, Samantha L / Welfer, Griffin A / Freudenthal, Bret D / Opresko, Patricia L

DNA repair

2021 Volume 107, Page(s) 103198

Abstract: Telomeres at the ends of linear chromosomes are essential for genome maintenance and sustained cellular proliferation, but shorten with each cell division. Telomerase, a specialized reverse transcriptase with its own integral RNA template, compensates ... ...

Abstract	Telomeres at the ends of linear chromosomes are essential for genome maintenance and sustained cellular proliferation, but shorten with each cell division. Telomerase, a specialized reverse transcriptase with its own integral RNA template, compensates for this by lengthening the telomeric 3' single strand overhang. Mammalian telomerase has the unique ability to processively synthesize multiple GGTTAG repeats, by translocating along its product and reiteratively copying the RNA template, termed repeat addition processivity (RAP). This unusual form of processivity is distinct from the nucleotide addition processivity (NAP) shared by all other DNA polymerases. In this review, we focus on the minimally active human telomerase catalytic core consisting of the telomerase reverse transcriptase (TERT) and the integral RNA (TR), which catalyzes DNA synthesis. We review the mechanisms by which oxidatively damaged nucleotides, and anti-viral and anti-cancer nucleotide drugs affect the telomerase catalytic cycle. Finally, we offer perspective on how we can leverage telomerase's unique properties, and advancements in understanding of telomerase catalytic mechanism, to selectively manipulate telomerase activity with therapeutics, particularly in cancer treatment.
MeSH term(s)	Telomerase
Chemical Substances	Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2021-07-31
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2021.103198
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Jg. 1995 - 2021: Lesesall (2.OG)
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Article ; Online: Oxidative guanine base damage plays a dual role in regulating productive ALT-associated homology-directed repair

Sanjana A. Thosar / Ryan P. Barnes / Ariana Detwiler / Ragini Bhargava / Anne Wondisford / Roderick J. O’Sullivan / Patricia L. Opresko

Cell Reports, Vol 43, Iss 1, Pp 113656- (2024)

2024

Abstract: Summary: Cancer cells maintain telomeres by upregulating telomerase or alternative lengthening of telomeres (ALT) via homology-directed repair at telomeric DNA breaks. 8-Oxoguanine (8oxoG) is a highly prevalent endogenous DNA lesion in telomeric ... ...

Abstract	Summary: Cancer cells maintain telomeres by upregulating telomerase or alternative lengthening of telomeres (ALT) via homology-directed repair at telomeric DNA breaks. 8-Oxoguanine (8oxoG) is a highly prevalent endogenous DNA lesion in telomeric sequences, altering telomere structure and telomerase activity, but its impact on ALT is unclear. Here, we demonstrate that targeted 8oxoG formation at telomeres stimulates ALT activity and homologous recombination specifically in ALT cancer cells. Mechanistically, an acute 8oxoG induction increases replication stress, as evidenced by increased telomere fragility and ATR kinase activation at ALT telomeres. Furthermore, ALT cells are more sensitive to chronic telomeric 8oxoG damage than telomerase-positive cancer cells, consistent with increased 8oxoG-induced replication stress. However, telomeric 8oxoG production in G2 phase, when ALT telomere elongation occurs, impairs telomeric DNA synthesis. Our study demonstrates that a common oxidative base lesion has a dual role in regulating ALT depending on when the damage arises in the cell cycle.
Keywords	CP: Molecular biology ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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