scholarly journals Erratum: Corrigendum: DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Francesca Rossiello ◽  
Julio Aguado ◽  
Sara Sepe ◽  
Fabio Iannelli ◽  
Quan Nguyen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Response Inhibition ◽  
Telomeric Dna ◽  
Damage Response

scholarly journals DNA Damage-Induced Phosphorylation of TRF2 Is Required for the Fast Pathway of DNA Double-Strand Break Repair

2009 ◽  
Vol 29 (13) ◽  
pp. 3597-3604 ◽  
Author(s):  
Nazmul Huda ◽  
Hiromi Tanaka ◽  
Marc S. Mendonca ◽  
David Gilley
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Functional Role ◽  
Strand Break ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Damage Response ◽  
Fast Pathway

ABSTRACT Protein kinases of the phosphatidylinositol 3-kinase-like kinase family, originally known to act in maintaining genomic integrity via DNA repair pathways, have been shown to also function in telomere maintenance. Here we focus on the functional role of DNA damage-induced phosphorylation of the essential mammalian telomeric DNA binding protein TRF2, which coordinates the assembly of the proteinaceous cap to disguise the chromosome end from being recognized as a double-stand break (DSB). Previous results suggested a link between the transient induction of human TRF2 phosphorylation at threonine 188 (T188) by the ataxia telangiectasia mutated protein kinase (ATM) and the DNA damage response. Here, we report evidence that X-ray-induced phosphorylation of TRF2 at T188 plays a role in the fast pathway of DNA DSB repair. These results connect the highly transient induction of human TRF2 phosphorylation to the DNA damage response machinery. Thus, we find that a protein known to function in telomere maintenance, TRF2, also plays a functional role in DNA DSB repair.

scholarly journals The evolution of metazoan shelterin

2021 ◽  
Author(s):  
Logan R. Myler ◽  
Charles G. Kinzig ◽  
Nanda K. Sasi ◽  
George Zakusilo ◽  
Sarah W. Cai ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Dna Binding Proteins ◽  
Telomeric Dna ◽  
Evolutionary Origins ◽  
Variable Nature ◽  
Damage Response ◽  
Unicellular Organisms ◽  
Ob Fold ◽  
Regulate Telomere Length

The mammalian telomeric shelterin complex—comprised of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1—blocks the DNA damage response at chromosome ends and interacts with telomerase and the CST complex to regulate telomere length. The evolutionary origins of shelterin are unclear, partly because unicellular organisms have distinct telomeric proteins. Here, we describe the evolution of metazoan shelterin, showing that TRF1 emerged in vertebrates upon duplication of a TRF2-like ancestor. TRF1 and TRF2 diverged rapidly during vertebrate evolution through the acquisition of new domains and interacting factors. Vertebrate shelterin is also distinguished by the presence of an HJRL domain in the split C-terminal OB fold of POT1, whereas invertebrate POT1s carry inserts of variable nature. Importantly, the data reveal that, apart from the primate and rodent POT1 orthologs, all metazoan POT1s are predicted to have a fourth OB fold at their N termini. Therefore, we propose that POT1 arose from a four-OB-fold ancestor, most likely an RPA70-like protein. This analysis provides insights into the biology of shelterin and its evolution from ancestral telomeric DNA-binding proteins.

scholarly journals Functional Dissection of Human and Mouse POT1 Proteins

2008 ◽  
Vol 29 (2) ◽  
pp. 471-482 ◽  
Author(s):  
Wilhelm Palm ◽  
Dirk Hockemeyer ◽  
Tatsuya Kibe ◽  
Titia de Lange
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Dna Damage Response ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Telomeric Dna ◽  
C Terminus ◽  
Damage Response ◽  
End Resection

ABSTRACT The single-stranded telomeric DNA binding protein POT1 protects mammalian chromosome ends from the ATR-dependent DNA damage response, regulates telomerase-mediated telomere extension, and limits 5′-end resection at telomere termini. Whereas most mammals have a single POT1 gene, mice have two POT1 proteins that are functionally distinct. POT1a represses the DNA damage response, and POT1b controls 5′-end resection. In contrast, as we report here, POT1a and POT1b do not differ in their ability to repress telomere recombination. By swapping domains, we show that the DNA binding domain of POT1a specifies its ability to repress the DNA damage response. However, no differences were detected in the in vitro DNA binding features of POT1a and POT1b. In contrast to the repression of ATR signaling by POT1a, the ability of POT1b to control 5′-end resection was found to require two regions in the C terminus, one corresponding to the TPP1 binding domain and a second representing a new domain located between amino acids (aa) 300 and 350. Interestingly, the DNA binding domain of human POT1 can replace that of POT1a to repress ATR signaling, and the POT1b region from aa 300 to 350 required for the regulation of the telomere terminus is functionally conserved in human POT1. Thus, human POT1 combines the features of POT1a and POT1b.

scholarly journals TRF1 prevents permissive DNA damage response, recombination and Break Induced Replication at telomeres

2019 ◽  
Author(s):  
Rosa Maria Porreca ◽  
Pui Pik Law ◽  
Emilia Herrera-Moyano ◽  
Roser Gonzalez-Franco ◽  
Alex Montoya ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Dna Recombination ◽  
Protein Composition ◽  
Telomeric Dna ◽  
Chromatin Remodelers ◽  
Damage Response ◽  
Telomere Replication ◽  
Break Induced Replication ◽  
Chromatin Rearrangement

AbstractTelomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that telomeres lacking TRF1 undergo protein composition reorganisation associated with a DNA damage response and chromatin remodelers. Surprisingly, TRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for TRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.

Spontaneous occurrence of telomeric DNA damage response in the absence of chromosome fusions

2009 ◽  
Vol 16 (12) ◽  
pp. 1244-1251 ◽  
Author(s):  
Anthony J Cesare ◽  
Zeenia Kaul ◽  
Scott B Cohen ◽  
Christine E Napier ◽  
Hilda A Pickett ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Telomeric Dna ◽  
Damage Response ◽  
Chromosome Fusions ◽  
Spontaneous Occurrence

scholarly journals Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation

2012 ◽  
Vol 14 (4) ◽  
pp. 355-365 ◽  
Author(s):  
Marzia Fumagalli ◽  
Francesca Rossiello ◽  
Michela Clerici ◽  
Sara Barozzi ◽  
Davide Cittaro ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Telomeric Dna ◽  
Damage Response ◽  
Response Activation

Triptolide sensitizes breast cancer cells to Doxorubicin through the DNA damage response inhibition

2018 ◽  
Vol 57 (6) ◽  
pp. 807-814 ◽  
Author(s):  
Yu Deng ◽  
Fulun Li ◽  
Pinglin He ◽  
Yafei Yang ◽  
Jin Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Response Inhibition ◽  
Breast Cancer Cells ◽  
Damage Response

scholarly journals DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Francesca Rossiello ◽  
Julio Aguado ◽  
Sara Sepe ◽  
Fabio Iannelli ◽  
Quan Nguyen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cultured Cells ◽  
Telomeric Dna ◽  
Cellular Events ◽  
Mouse Tissues ◽  
Damage Response ◽  
Dna Strands ◽  
Non Coding Rnas

Abstract The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage. Recently, site-specific small non-coding RNAs, also termed DNA damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Dysfunctional telomeres activate DDR in ageing, cancer and an increasing number of identified pathological conditions. Here we show that, in mammals, telomere dysfunction induces the transcription of telomeric DDRNAs (tDDRNAs) and their longer precursors from both DNA strands. DDR activation and maintenance at telomeres depend on the biogenesis and functions of tDDRNAs. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues. In summary, these results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs.

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