TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells
Abstract The telomere repeat-containing RNA (TERRA) forms R-loops to promote homology-directed DNA synthesis in the alternative lengthening of telomere (ALT) pathway. Here we report that TERRA contributes to ALT via interacting with the lysine-specific demethylase 1A (LSD1 or KDM1A). We show that LS...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46509-z |
| _version_ | 1827321392675160064 |
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| author | Meng Xu Dulmi Senanayaka Rongwei Zhao Tafadzwa Chigumira Astha Tripathi Jason Tones Rachel M. Lackner Anne R. Wondisford Laurel N. Moneysmith Alexander Hirschi Sara Craig Sahar Alishiri Roderick J. O’Sullivan David M. Chenoweth Nicholas J. Reiter Huaiying Zhang |
| author_facet | Meng Xu Dulmi Senanayaka Rongwei Zhao Tafadzwa Chigumira Astha Tripathi Jason Tones Rachel M. Lackner Anne R. Wondisford Laurel N. Moneysmith Alexander Hirschi Sara Craig Sahar Alishiri Roderick J. O’Sullivan David M. Chenoweth Nicholas J. Reiter Huaiying Zhang |
| author_sort | Meng Xu |
| collection | DOAJ |
| description | Abstract The telomere repeat-containing RNA (TERRA) forms R-loops to promote homology-directed DNA synthesis in the alternative lengthening of telomere (ALT) pathway. Here we report that TERRA contributes to ALT via interacting with the lysine-specific demethylase 1A (LSD1 or KDM1A). We show that LSD1 localizes to ALT telomeres in a TERRA dependent manner and LSD1 function in ALT is largely independent of its demethylase activity. Instead, LSD1 promotes TERRA recruitment to ALT telomeres via RNA binding. In addition, LSD1 and TERRA undergo phase separation, driven by interactions between the RNA binding properties of LSD1 and the G-quadruplex structure of TERRA. Importantly, the formation of TERRA-LSD1 condensates enriches the R-loop stimulating protein Rad51AP1 and increases TERRA-containing R-loops at telomeres. Our findings suggest that LSD1-TERRA phase separation enhances the function of R-loop regulatory molecules for ALT telomere maintenance, providing a mechanism for how the biophysical properties of histone modification enzyme-RNA interactions impact chromatin function. |
| first_indexed | 2024-04-25T01:05:21Z |
| format | Article |
| id | doaj.art-dcb692d3221c47b5818c21d0c3bc1b6d |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-25T01:05:21Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-dcb692d3221c47b5818c21d0c3bc1b6d2024-03-10T12:17:42ZengNature PortfolioNature Communications2041-17232024-03-0115111910.1038/s41467-024-46509-zTERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cellsMeng Xu0Dulmi Senanayaka1Rongwei Zhao2Tafadzwa Chigumira3Astha Tripathi4Jason Tones5Rachel M. Lackner6Anne R. Wondisford7Laurel N. Moneysmith8Alexander Hirschi9Sara Craig10Sahar Alishiri11Roderick J. O’Sullivan12David M. Chenoweth13Nicholas J. Reiter14Huaiying Zhang15Department of Biology, Carnegie Mellon UniversityKlingler College of Arts and Sciences, Department of Chemistry, Marquette UniversityDepartment of Biology, Carnegie Mellon UniversityDepartment of Biology, Carnegie Mellon UniversityDepartment of Biology, Carnegie Mellon UniversityDepartment of Biology, Carnegie Mellon UniversityDepartment of Chemistry, University of PennsylvaniaDepartment of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of PittsburghKlingler College of Arts and Sciences, Department of Chemistry, Marquette UniversityCepheid DiagnosticsKlingler College of Arts and Sciences, Department of Chemistry, Marquette UniversityKlingler College of Arts and Sciences, Department of Chemistry, Marquette UniversityDepartment of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of PittsburghDepartment of Chemistry, University of PennsylvaniaKlingler College of Arts and Sciences, Department of Chemistry, Marquette UniversityDepartment of Biology, Carnegie Mellon UniversityAbstract The telomere repeat-containing RNA (TERRA) forms R-loops to promote homology-directed DNA synthesis in the alternative lengthening of telomere (ALT) pathway. Here we report that TERRA contributes to ALT via interacting with the lysine-specific demethylase 1A (LSD1 or KDM1A). We show that LSD1 localizes to ALT telomeres in a TERRA dependent manner and LSD1 function in ALT is largely independent of its demethylase activity. Instead, LSD1 promotes TERRA recruitment to ALT telomeres via RNA binding. In addition, LSD1 and TERRA undergo phase separation, driven by interactions between the RNA binding properties of LSD1 and the G-quadruplex structure of TERRA. Importantly, the formation of TERRA-LSD1 condensates enriches the R-loop stimulating protein Rad51AP1 and increases TERRA-containing R-loops at telomeres. Our findings suggest that LSD1-TERRA phase separation enhances the function of R-loop regulatory molecules for ALT telomere maintenance, providing a mechanism for how the biophysical properties of histone modification enzyme-RNA interactions impact chromatin function.https://doi.org/10.1038/s41467-024-46509-z |
| spellingShingle | Meng Xu Dulmi Senanayaka Rongwei Zhao Tafadzwa Chigumira Astha Tripathi Jason Tones Rachel M. Lackner Anne R. Wondisford Laurel N. Moneysmith Alexander Hirschi Sara Craig Sahar Alishiri Roderick J. O’Sullivan David M. Chenoweth Nicholas J. Reiter Huaiying Zhang TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells Nature Communications |
| title | TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells |
| title_full | TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells |
| title_fullStr | TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells |
| title_full_unstemmed | TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells |
| title_short | TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells |
| title_sort | terra lsd1 phase separation promotes r loop formation for telomere maintenance in alt cancer cells |
| url | https://doi.org/10.1038/s41467-024-46509-z |
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