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

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

iScience (May 2020)

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

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

Affiliations

Rosaline Y.C. Hsu: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601S Goodwin Avenue, Urbana, IL 61801, USA
Yo-Chuen Lin: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601S Goodwin Avenue, Urbana, IL 61801, USA
Christophe Redon: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda MD 20892, USA
Qinyu Sun: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601S Goodwin Avenue, Urbana, IL 61801, USA
Deepak K. Singh: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601S Goodwin Avenue, Urbana, IL 61801, USA
Yating Wang: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601S Goodwin Avenue, Urbana, IL 61801, USA
Vasudha Aggarwal: Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD 21205, USA
Jaba Mitra: Materials Engineering Department, UIUC, Urbana, IL 61801, USA
Abhijith Matur: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601S Goodwin Avenue, Urbana, IL 61801, USA
Branden Moriarity: Department of Pediatrics, University of Minnesota, MN 55455 USA
Taekjip Ha: Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, MD 21205, USA
Mirit I. Aladjem: Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda MD 20892, USA
Kannanganattu V. Prasanth: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601S Goodwin Avenue, Urbana, IL 61801, USA; Cancer Center at Illinois, UIUC, Urbana, IL 61801, USA
Supriya G. Prasanth: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601S Goodwin Avenue, Urbana, IL 61801, USA; Cancer Center at Illinois, UIUC, Urbana, IL 61801, USA; Corresponding author

Journal volume & issue: Vol. 23, no. 5

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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