ORCA/LRWD1 Regulates Homologous Recombination at ALT-Telomeres by Modulating Heterochromatin Organization

Summary: Telomeres are maintained by telomerase or in a subset of cancer cells by a homologous recombination (HR)-based mechanism, Alternative Lengthening of Telomeres (ALT). The mechanisms regulating telomere-homeostasis in ALT cells remain unclear. We report that a replication initiator protein, O...

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Bibliographic Details
Published in:iScience
Main Authors: Rosaline Y.C. Hsu, Yo-Chuen Lin, Christophe Redon, Qinyu Sun, Deepak K. Singh, Yating Wang, Vasudha Aggarwal, Jaba Mitra, Abhijith Matur, Branden Moriarity, Taekjip Ha, Mirit I. Aladjem, Kannanganattu V. Prasanth, Supriya G. Prasanth
Format: Article in Journal/Newspaper
Language:English
Published: Elsevier 2020
Subjects:
Biological Sciences
Molecular Biology
Chromosome Organization
Molecular Structure
Science
Q
Orca
Online Access:https://doi.org/10.1016/j.isci.2020.101038
https://doaj.org/article/ffd7c76cb510474a8bfbcdf73ec5267e
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Summary:Summary: Telomeres are maintained by telomerase or in a subset of cancer cells by a homologous recombination (HR)-based mechanism, Alternative Lengthening of Telomeres (ALT). The mechanisms regulating telomere-homeostasis in ALT cells remain unclear. We report that a replication initiator protein, Origin Recognition Complex-Associated (ORCA/LRWD1), by localizing at the ALT-telomeres, modulates HR activity. ORCA's localization to the ALT-telomeres is facilitated by its interaction to SUMOylated shelterin components. The loss of ORCA in ALT-positive cells elevates the levels of two mediators of HR, RPA and RAD51, and consistent with this, we observe increased ALT-associated promyelocytic leukemia body formation and telomere sister chromatid exchange. ORCA binds to RPA and modulates the association of RPA to telomeres. Finally, the loss of ORCA causes global chromatin decondensation, including at the telomeres. Our results demonstrate that ORCA acts as an inhibitor of HR by modulating RPA binding to ssDNA and inducing chromatin compaction.

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