期刊
ELIFE
卷 4, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.06496
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- National Institutes of Health (NIH) [F31 (CA180616), 1RO1GM088252, 1RO1GM099669]
- National Science Foundation (NSF) [1243372]
- Howard Hughes Medical Institute (HHMI)
- Agence Nationale de la Recherche
- AFM-Telethon (French Muscular Dystrophy Association)
- Fondation ARC pour la Recherche sur le Cancer
- Institut national du cancer [2012-1-PLBIO]
- Ministere de l'Education Nationale, de l'Enseignement Superieur et de la Recherche
- American Cancer Society [RSG 11-174-01RMC]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1243372] Funding Source: National Science Foundation
Heterochromatic domains are enriched with repressive histone marks, including histone H3 lysine 9 methylation, written by lysine methyltransferases (KMTs). The pre-replication complex protein, origin recognition complex-associated (ORCA/LRWD1), preferentially localizes to heterochromatic regions in post-replicated cells. Its role in heterochromatin organization remained elusive. ORCA recognizes methylated H3K9 marks and interacts with repressive KMTs, including G9a/GLP and Suv39H1 in a chromatin context-dependent manner. Single-molecule pull-down assays demonstrate that ORCA-ORC (Origin Recognition Complex) and multiple H3K9 KMTs exist in a single complex and that ORCA stabilizes H3K9 KMT complex. Cells lacking ORCA show alterations in chromatin architecture, with significantly reduced H3K9 di- and tri-methylation at specific chromatin sites. Changes in heterochromatin structure due to loss of ORCA affect replication timing, preferentially at the late-replicating regions. We demonstrate that ORCA acts as a scaffold for the establishment of H3K9 KMT complex and its association and activity at specific chromatin sites is crucial for the organization of heterochromatin structure.
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