ORCA/LRWD1 Regulates Homologous Recombination at ALT-Telomeres by Modulating Heterochromatin Organization
ORCA/LRWD1 Regulates Homologous Recombination at ALT-Telomeres by Modulating Heterochromatin Organization
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DOI：
10.1016/j.isci.2020.101038
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发表时间：
2020-05-22
期刊：
影响因子：
5.8
通讯作者：
Prasanth, Supriya G.
中科院分区：
文献类型：
--
作者：
Hsu, Rosaline Y. C.;Lin, Yo-Chuen;Prasanth, Supriya G.
端粒由端粒酶维持，或通过基于同源重组 (HR) 的机制，即端粒替代延长 (ALT) 维持在癌细胞的子集中。 ALT 细胞端粒稳态的调节机制仍不清楚。我们报告复制起始蛋白，起源识别复合物相关 (ORCA/LRWD1)，通过定位于 ALT 端粒，调节 HR 活性。 ORCA 与 SUMO 化庇护蛋白成分的相互作用促进了其对 ALT 端粒的定位。 ALT 阳性细胞中 ORCA 的缺失提高了 HR、RPA 和 RAD51 两种介质的水平，与此一致，我们观察到 ALT 相关的早幼粒细胞白血病体形成和端粒姐妹染色单体交换增加。 ORCA 与 RPA 结合并调节 RPA 与端粒的关联。最后，ORCA 的缺失会导致整体染色质解浓缩，包括端粒处。我们的结果表明，ORCA 通过调节 RPA 与 ssDNA 的结合并诱导染色质压缩来充当 HR 抑制剂。
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.