Defective Repair of Uracil Causes Telomere Defects in Mouse Hematopoietic Cells

Vallabhaneni, Haritha; Zhou, Fang; Maul, Robert W.; Sarkar, Jaya; Yin, Jinhu; Lei, Ming; Harrington, Lea; Gearhart, Patricia J.; Liu, Yie

doi:10.1074/jbc.m114.607101

Cited by 23 publications

(25 citation statements)

References 70 publications

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“…There is a growing body of evidence indicating that uracil can exert significant effects on protein binding to DNA. These findings include (i) our previous report that multiple uracils silenced transcription from both HIV-1 LTR and CMV promoters in a cell line ( Weil et al, 2013 ), (ii) uracils within the origin of replication in HSV-1 perturb the binding of HSV-1 origin binding protein ( Focher et al, 1992 ), (iii) U/A pairs disrupt AP-1 transcription factor DNA binding ( Rogstad et al, 2002 ), (iv) singly uracilated DNA disrupts RNase H splicing specificity during reverse transcription Klarmann, 2003 , (v) U/A pairs perturb maintenance of telomere length in B cells by disruption of sheltrin binding ( Vallabhaneni et al, 2015 ), and (vi) one or two U/A base pairs within the specific cleavage site of some restriction enzymes prevents DNA strand cleavage ( Roberts et al, 2015 ). In addition, the abasic site product of uracil excision is known to exert a large negative effect on transcription ( Luhnsdorf et al, 2014 ) as would any mutations in transcription factor recognition sequences arising from error prone repair of excised uracils ( Shah et al, 2015 ; Emiliani, 1998 ).…”

Section: Discussionmentioning

confidence: 99%

Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells

Hansen

Ransom

Hesselberth

et al. 2016

eLife

130

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We report that a major subpopulation of monocyte-derived macrophages (MDMs) contains high levels of dUTP, which is incorporated into HIV-1 DNA during reverse transcription (U/A pairs), resulting in pre-integration restriction and post-integration mutagenesis. After entering the nucleus, uracilated viral DNA products are degraded by the uracil base excision repair (UBER) machinery with less than 1% of the uracilated DNA successfully integrating. Although uracilated proviral DNA showed few mutations, the viral genomic RNA was highly mutated, suggesting that errors occur during transcription. Viral DNA isolated from blood monocytes and alveolar macrophages (but not T cells) of drug-suppressed HIV-infected individuals also contained abundant uracils. The presence of viral uracils in short-lived monocytes suggests their recent infection through contact with virus producing cells in a tissue reservoir. These findings reveal new elements of a viral defense mechanism involving host UBER that may be relevant to the establishment and persistence of HIV-1 infection.DOI: http://dx.doi.org/10.7554/eLife.18447.001

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Section: Discussionmentioning

confidence: 99%

Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells

Hansen

Ransom

Hesselberth

et al. 2016

eLife

130

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“…Oxidative damages has been implicated as a primary cause of telomere shortening, evidenced by the observations that telomere attrition rate is significantly decreased when cells are grown in hypoxia condition or in the presence of antioxidant [11, 12]. In addition, both uracil residues and oxidized guanine derivatives are commonly present at telomeres [13–15]. Mounting evidence from both in vivo and in vitro studies suggests that BER is actively promoted at telomeres.…”

Section: Ber At Telomeresmentioning

confidence: 99%

“…Deficiency in UNG accumulates telomeric uracils and causes telomere defects including increased telomere fragility and aberrant telomere recombination in mouse hematopoietic cells [13]. Substituting thymine residues in a telomeric DNA substrate with uracils weakens POT1/TPP1 binding to substrates in vitro [13], indicating that telomere defects caused by UNG deficiency may be partially attributed to interference of POT1/TPP1 binding to damaged telomeric DNA.…”

Section: Ber At Telomeresmentioning

confidence: 99%

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DNA excision repair at telomeres

2015

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DNA damage is caused by either endogenous cellular metabolic processes such as hydrolysis, oxidation, alkylation, and DNA base mismatches, or exogenous sources including ultraviolet (UV) light, ionizing radiation, and chemical agents. Damaged DNA that is not properly repaired can lead to genomic instability, driving tumorigenesis. To protect genomic stability, mammalian cells have evolved highly conserved DNA repair mechanisms to remove and repair DNA lesions. Telomeres are composed of long tandem TTAGGG repeats located at the ends of chromosomes. Maintenance of functional telomeres is critical for preventing genome instability. The telomeric sequence possesses unique features that predispose telomeres to a variety of DNA damage induced by environmental genotoxins. This review briefly describes the relevance of excision repair pathways in telomere maintenance, with the focus on base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). By summarizing current knowledge on excision repair of telomere damage and outlining many unanswered questions, it is our hope to stimulate further interest in a better understanding of excision repair processes at telomeres and in how these processes contribute to telomere maintenance.

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“…Due to the presence of long arrays of TTAGGG repeats, uracil can appear in telomeric DNA by misincorporation of deoxyuridine triphosphate (dUTP) instead of deoxythymidine triphosphate (dTTP) opposite adenine or by deamination of cytosine to uracil opposite guanine (Krokan et al, 2002). Accumulation of uracil interferes with telomere homeostasis, and UNG-initiated BER is necessary for the preservation of telomere integrity (Vallabhaneni et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A common SNP in the UNG gene decreases ovarian cancer risk in BRCA2 mutation carriers

et al. 2019

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Single nucleotide polymorphisms ( SNP s) in DNA glycosylase genes involved in the base excision repair ( BER ) pathway can modify breast and ovarian cancer risk in BRCA 1 and BRCA 2 mutation carriers. We previously found that SNP rs34259 in the uracil‐ DNA glycosylase gene ( UNG ) might decrease ovarian cancer risk in BRCA 2 mutation carriers. In the present study, we validated this finding in a larger series of familial breast and ovarian cancer patients to gain insights into how this UNG variant exerts its protective effect. We found that rs34259 is associated with significant UNG downregulation and with lower levels of DNA damage at telomeres. In addition, we found that this SNP is associated with significantly lower oxidative stress susceptibility and lower uracil accumulation at telomeres in BRCA 2 mutation carriers. Our findings help to explain the association of this variant with a lower cancer risk in BRCA 2 mutation carriers and highlight the importance of genetic changes in BER pathway genes as modifiers of cancer susceptibility for BRCA 1 and BRCA 2 mutation carriers.

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Defective Repair of Uracil Causes Telomere Defects in Mouse Hematopoietic Cells

Cited by 23 publications

References 70 publications

Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells

Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells

DNA excision repair at telomeres

A common SNP in the UNG gene decreases ovarian cancer risk in BRCA2 mutation carriers

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