Telomeric protein TRF2 protects Holliday junctions with telomeric arms from displacement by the Werner syndrome helicase
| Autor: | Noah Buncher, Patricia L. Opresko, Gerald J. Nora |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Premature aging
congenital hereditary and neonatal diseases and abnormalities Werner Syndrome Helicase Telomere-Binding Proteins Genome Integrity Repair and Replication 03 medical and health sciences 0302 clinical medicine Genetics Holliday junction medicine Humans MYB Telomeric Repeat Binding Protein 2 education 030304 developmental biology Werner syndrome Telomere-binding protein 0303 health sciences education.field_of_study DNA Cruciform biology RecQ Helicases Helicase nutritional and metabolic diseases Telomere medicine.disease Molecular biology Cell biology Exodeoxyribonucleases 030220 oncology & carcinogenesis biology.protein |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | WRN protein loss causes Werner syndrome (WS), which is characterized by premature aging as well as genomic and telomeric instability. WRN prevents telomere loss, but the telomeric protein complex must regulate WRN activities to prevent aberrant telomere processing. Telomere-binding TRF2 protein inhibits telomere t-loop deletion by blocking Holliday junction (HJ) resolvase cleavage activity, but whether TRF2 also modulates HJ displacement at t-loops is unknown. In this study, we used multiplex fluorophore imaging to track the fate of individual strands of HJ substrates. We report the novel finding that TRF2 inhibits WRN helicase strand displacement of HJs with telomeric repeats in duplex arms, but unwinding of HJs with a telomeric center or lacking telomeric sequence is unaffected. These data, together with results using TRF2 fragments and TRF2 HJ binding assays, indicate that both the TRF2 B- and Myb domains are required to inhibit WRN HJ activity. We propose a novel model whereby simultaneous binding of the TRF2 B-domain to the HJ core and the Myb domain to telomeric arms promote and stabilize HJs in a stacked arm conformation that is unfavorable for unwinding. Our biochemical study provides a mechanistic basis for the cellular findings that TRF2 regulates WRN activity at telomeres. |
| Databáze: | OpenAIRE |
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