scholarly journals Analysis of Ustilago maydis pot1 reveals context-dependent, dichotomous regulation of homology-directed DNA repair factors by a telomere protein

2021 ◽  
Author(s):  
Syed S. Zahid ◽  
Sarah Aloe ◽  
Jeanette Sutherland ◽  
William K. Holloman ◽  
Neal F. Lue
Keyword(s):  
Dna Repair ◽  
Transcriptional Repression ◽  
Ustilago Maydis ◽  
Telomere Maintenance ◽  
Telomere Repeat ◽  
Homology Directed Repair ◽  
Telomere Protein ◽  
Genetic Mechanisms ◽  
Context Dependent ◽  
Telomere Regulation

AbstractThe telomere G-strand binding protein Pot1 plays multifaceted roles in telomere maintenance and protection. We examined the biochemical activity and genetic mechanisms of Pot1 in Ustilago maydis, a fungal model that recapitulates key features of mammalian telomere regulation. We found that U. maydis Pot1 binds directly to Rad51 and regulates the latter’s strand exchange activity. Deleting an N-terminal domain of Pot1 implicated in Rad51-binding caused telomere shortening, suggesting that Pot1-Rad51 interaction facilitates telomere replication. Depleting Pot1 through transcriptional repression triggered growth arrest as well as rampant recombination, leading to multiple telomere aberrations. In addition, telomere repeat RNAs transcribed from both the G- and C-strand were dramatically up-regulated, and this was accompanied by elevated levels of telomere RNA-DNA hybrids. Telomere abnormalities of pot1-deficient cells were suppressed, and cell viability was rescued by the deletion of rad51 or brh2 (the BRCA2 ortholog), indicating that homology-directed repair (HDR) proteins are key mediators of telomere aberrations and cellular toxicity. Together, these observations underscore the complex physical and functional interactions between Pot1 and DNA repair factors, leading to context-dependent and dichotomous effects of HDR proteins on telomere maintenance and protection.

scholarly journals Structurally distinct telomere-binding proteins in Ustilago maydis execute non-overlapping functions in telomere replication, recombination, and protection

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Eun Young Yu ◽  
Syed S. Zahid ◽  
Swapna Ganduri ◽  
Jeanette H. Sutherland ◽  
Min Hsu ◽  
...  
Keyword(s):  
Functional Diversity ◽  
Transcriptional Repression ◽  
Binding Proteins ◽  
Ustilago Maydis ◽  
Sequence Specificity ◽  
Telomere Repeat ◽  
Growth Defects ◽  
Domain Structures ◽  
Telomere Protein ◽  
Telomere Replication

AbstractDuplex telomere binding proteins exhibit considerable structural and functional diversity in fungi. Herein we interrogate the activities and functions of two Myb-containing, duplex telomere repeat-binding factors in Ustilago maydis, a basidiomycete that is evolutionarily distant from the standard fungi. These two telomere-binding proteins, UmTay1 and UmTrf2, despite having distinct domain structures, exhibit comparable affinities and sequence specificity for the canonical telomere repeats. UmTay1 specializes in promoting telomere replication and an ALT-like pathway, most likely by modulating the helicase activity of Blm. UmTrf2, in contrast, is critical for telomere protection; transcriptional repression of Umtrf2 leads to severe growth defects and profound telomere aberrations. Comparative analysis of UmTay1 homologs in different phyla reveals broad functional diversity for this protein family and provides a case study for how DNA-binding proteins can acquire and lose functions at various chromosomal locations. Our findings also point to stimulatory effect of telomere protein on ALT in Ustilago maydis that may be conserved in other systems.

scholarly journals Structurally distinct duplex telomere repeat-binding proteins in Ustilago maydis execute specialized, non-overlapping functions in telomere recombination and telomere protection

2020 ◽  
Author(s):  
Eun Young Yu ◽  
Syed Zahid ◽  
Min Hsu ◽  
Jeanette Sutherland ◽  
William K. Holloman ◽  
...  
Keyword(s):  
Functional Diversity ◽  
Transcriptional Repression ◽  
Binding Proteins ◽  
Critical Role ◽  
Ustilago Maydis ◽  
Sequence Specificity ◽  
Telomere Repeat ◽  
Telomere Protection ◽  
Telomere Protein ◽  
Telomere Replication

AbstractDuplex telomere binding proteins exhibit considerable structural and functional diversity in different phyla. Herein we address the distinct properties and functions of two Myb-containing, duplex telomere repeat-binding factors in Ustilago maydis, a basidiomycete fungus that is evolutionarily distant from the standard budding and fission yeasts. The two telomere-binding proteins in U. maydis, named UmTrf1 and UmTrf2, have different domain organizations and belong to distinct protein families with different phylogenetic distributions. Despite these differences, they exhibit comparable affinities and similar sequence specificity for the canonical, 6-base-pair telomere repeats. Deletion of trf1 triggers preferential loss of long telomere tracts, suggesting a role for the encoded protein in promoting telomere replication. Trf1 loss also partially suppresses the ALT-like phenotypes of ku70-deficient mutants, suggesting a novel role for a telomere protein in stimulating ALT-related pathways. In keeping with these ideas, we found that purified Trf1 can modulate the helicase activity of Blm, a conserved telomere replication and recombination factor. In contrast, trf2 appears to be essential and transcriptional repression of this gene leads to severe growth defects and profound telomere aberrations that encompass telomere length heterogeneity, accumulation of extrachromosomal telomere repeats such as C-circles, and high levels of single-stranded telomere DNA. These observations support a critical role for UmTrf2 in telomere protection. Together, our findings point to a unique, unprecedented division of labor between the two major duplex telomere repeat-binding factors in Ustilago maydis. Comparative analysis of UmTrf1 homologs in different phyla reveals a high degree of functional diversity for this protein family, and provides a case study for how a sequence-specific DNA binding protein can acquire and lose functions at different chromosomal locations.

scholarly journals Duplex Telomere-Binding Proteins in Fungi With Canonical Telomere Repeats: New Lessons in the Rapid Evolution of Telomere Proteins

2021 ◽  
Vol 12 ◽  
Author(s):  
Neal F. Lue
Keyword(s):  
Fission Yeast ◽  
Functional Divergence ◽  
Repeat Unit ◽  
Rapid Evolution ◽  
Binding Activity ◽  
Protein Family ◽  
Telomere Maintenance ◽  
Telomere Repeat ◽  
Telomere Sequence ◽  
Telomere Protein

The telomere protein assemblies in different fungal lineages manifest quite profound structural and functional divergence, implying a high degree of flexibility and adaptability. Previous comparative analyses of fungal telomeres have focused on the role of telomere sequence alterations in promoting the evolution of corresponding proteins, particularly in budding and fission yeast. However, emerging evidence suggests that even in fungi with the canonical 6-bp telomere repeat unit, there are significant remodeling of the telomere assembly. Indeed, a new protein family can be recruited to serve dedicated telomere functions, and then experience subsequent loss in sub-branches of the clade. An especially interesting example is the Tay1 family of proteins, which emerged in fungi prior to the divergence of basidiomycetes from ascomycetes. This relatively recent protein family appears to have acquired its telomere DNA-binding activity through the modification of another Myb-containing protein. Members of the Tay1 family evidently underwent rather dramatic functional diversification, serving, e.g., as transcription factors in fission yeast while acting to promote telomere maintenance in basidiomycetes and some hemi-ascomycetes. Remarkably, despite its distinct structural organization and evolutionary origin, a basidiomycete Tay1 appears to promote telomere replication using the same mechanism as mammalian TRF1, i.e., by recruiting and regulating Blm helicase activity. This apparent example of convergent evolution at the molecular level highlight the ability of telomere proteins to acquire new interaction targets. The remarkable evolutionary history of Tay1 illustrates the power of protein modularity and the facile acquisition of nucleic acid/protein-binding activity to promote telomere flexibility.

scholarly journals Brh2 and Rad51 promote telomere maintenance in Ustilago maydis, a new model system of DNA repair proteins at telomeres

DNA Repair ◽  
2013 ◽  
Vol 12 (7) ◽  
pp. 472-479 ◽  
Author(s):  
Eun Young Yu ◽  
Milorad Kojic ◽  
William K. Holloman ◽  
Neal F. Lue
Keyword(s):  
Dna Repair ◽  
Ustilago Maydis ◽  
Model System ◽  
Telomere Maintenance ◽  
New Model ◽  
Dna Repair Proteins

scholarly journals Deficiency in Poly(ADP-ribose) Polymerase-1 (PARP-1) Accelerates Aging and Spontaneous Carcinogenesis in Mice

2008 ◽  
Vol 2008 ◽  
pp. 1-11 ◽  
Author(s):  
Tatiana S. Piskunova ◽  
Maria N. Yurova ◽  
Anton I. Ovsyannikov ◽  
Anna V. Semenchenko ◽  
Mark A. Zabezhinski ◽  
...  
Keyword(s):  
Dna Repair ◽  
Life Span ◽  
Soft Tissues ◽  
Telomere Maintenance ◽  
Biological Aging ◽  
Spontaneous Tumors ◽  
Uterine Tumors ◽  
Dna Repair Gene ◽  
Spontaneous Carcinogenesis ◽  
Parp 1

Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosyl)ation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosyl)ation and PARP-1 may also play an important role in aging. Here we show that PARP- mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP- mice. The incidence of spontaneous tumors in both PARP- and PARP- groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP- mice than PARP- mice (72% and 49%, resp.; .05). In addition, spontaneous tumors appear earlier in PARP- mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.

scholarly journals Recent Advances in Understanding Werner Syndrome

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1779 ◽  
Author(s):  
Raghavendra A. Shamanna ◽  
Deborah L. Croteau ◽  
Jong-Hyuk Lee ◽  
Vilhelm A. Bohr
Keyword(s):  
Dna Repair ◽  
Stem Cell ◽  
Genome Stability ◽  
Werner Syndrome ◽  
Genetic Disorder ◽  
Accelerated Aging ◽  
Nutrient Sensing ◽  
Telomere Maintenance ◽  
Telomere Attrition ◽  
Recent Advances

Aging, the universal phenomenon, affects human health and is the primary risk factor for major disease pathologies. Progeroid diseases, which mimic aging at an accelerated rate, have provided cues in understanding the hallmarks of aging. Mutations in DNA repair genes as well as in telomerase subunits are known to cause progeroid syndromes. Werner syndrome (WS), which is characterized by accelerated aging, is an autosomal-recessive genetic disorder. Hallmarks that define the aging process include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulation of nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. WS recapitulates these hallmarks of aging and shows increased incidence and early onset of specific cancers. Genome integrity and stability ensure the normal functioning of the cell and are mainly guarded by the DNA repair machinery and telomeres. WRN, being a RecQ helicase, protects genome stability by regulating DNA repair pathways and telomeres. Recent advances in WS research have elucidated WRN’s role in DNA repair pathway choice regulation, telomere maintenance, resolution of complex DNA structures, epigenetic regulation, and stem cell maintenance.

scholarly journals Collaboration in the actions of Brh2 with resolving functions during DNA repair and replication stress in Ustilago maydis

DNA Repair ◽  
2018 ◽  
Vol 63 ◽  
pp. 47-55
Author(s):  
Milorad Kojic ◽  
Mira Milisavljevic ◽  
William K. Holloman
Keyword(s):  
Dna Repair ◽  
Replication Stress ◽  
Ustilago Maydis

scholarly journals ATM‐Dependent Recruitment of BRD7 is required for Transcriptional Repression and DNA Repair at DNA Breaks Flanking Transcriptional Active Regions

2020 ◽  
Vol 7 (20) ◽  
pp. 2000157
Author(s):  
Kaishun Hu ◽  
Yu Li ◽  
Wenjing Wu ◽  
Limin Xie ◽  
Haiyan Yan ◽  
...  
Keyword(s):  
Dna Repair ◽  
Transcriptional Repression ◽  
Active Regions ◽  
Dna Breaks

scholarly journals Impact of hypoxia on DNA repair and genome integrity

Mutagenesis ◽  
2019 ◽  
Vol 35 (1) ◽  
pp. 61-68 ◽  
Author(s):  
Alanna R Kaplan ◽  
Peter M Glazer
Keyword(s):  
Dna Repair ◽  
Cancer Progression ◽  
Base Excision Repair ◽  
Mutation Frequency ◽  
Excision Repair ◽  
Tumour Microenvironment ◽  
Genome Integrity ◽  
Future Directions ◽  
Homology Directed Repair ◽  
Base Excision

Abstract Hypoxia is a hallmark of the tumour microenvironment with profound effects on tumour biology, influencing cancer progression, the development of metastasis and patient outcome. Hypoxia also contributes to genomic instability and mutation frequency by inhibiting DNA repair pathways. This review summarises the diverse mechanisms by which hypoxia affects DNA repair, including suppression of homology-directed repair, mismatch repair and base excision repair. We also discuss the effects of hypoxia mimetics and agents that induce hypoxia on DNA repair, and we highlight areas of potential clinical relevance as well as future directions.

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