Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A
Abstract
Repair of DNA double-strand breaks (DSBs) must be orchestrated properly within diverse chromatin domains in order to maintain genetic stability. Euchromatin and heterochromatin domains display major differences in histone modifications, biophysical properties, and spatiotemporal dynamics of DSB repair. However, it is unclear whether differential histone-modifying activities are required for DSB repair in these distinct domains. Here, we showed previously that the Drosophila melanogaster KDM4A (dKDM4A) histone demethylase is required for heterochromatic DSB mobility. Here we used locus-specific DSB induction in Drosophila animal tissues and cultured cells to more deeply interrogate the impact of dKDM4A on chromatin changes, temporal progression, and pathway utilization during DSB repair. We found that dKDM4A promotes the demethylation of heterochromatin-associated histone marks at DSBs in heterochromatin but not euchromatin. Most importantly, we demonstrate that dKDM4A is required to complete DSB repair in a timely manner and regulate the relative utilization of homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways but exclusively for heterochromatic DSBs. We conclude that the temporal kinetics and pathway utilization during heterochromatic DSB repair depend on dKDM4A-dependent demethylation of heterochromatic histone marks. Thus, distinct pre-existing chromatin states require specialized epigenetic alterations to ensure proper DSB repair.
- Authors:
-
[1];
[1]
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States); Innovative Genomics Inst., Berkeley, CA (United States)
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH); Dutch Cancer Society; Innovation Genomics Institute
- OSTI Identifier:
- 1604663
- Grant/Contract Number:
- AC02-05CH11231; R01 GM086613; R01 GM117420
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Genes & Development
- Additional Journal Information:
- Journal Volume: 33; Journal Issue: 1-2; Journal ID: ISSN 0890-9369
- Publisher:
- Cold Springs Harbor Laboratory Press
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; drosophila; H3K56me3; H3K9me3; dkDM4A; double-strand breaks; euchromatin; heterochromatin; histone demethylation; homologous recombination; repair pathway choice
Citation Formats
Janssen, Aniek, Colmenares, Serafin U., Lee, Timothy, and Karpen, Gary H. Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A. United States: N. p., 2018.
Web. doi:10.1101/gad.317537.118.
Janssen, Aniek, Colmenares, Serafin U., Lee, Timothy, & Karpen, Gary H. Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A. United States. https://doi.org/10.1101/gad.317537.118
Janssen, Aniek, Colmenares, Serafin U., Lee, Timothy, and Karpen, Gary H. Fri .
"Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A". United States. https://doi.org/10.1101/gad.317537.118. https://www.osti.gov/servlets/purl/1604663.
@article{osti_1604663,
title = {Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A},
author = {Janssen, Aniek and Colmenares, Serafin U. and Lee, Timothy and Karpen, Gary H.},
abstractNote = {Repair of DNA double-strand breaks (DSBs) must be orchestrated properly within diverse chromatin domains in order to maintain genetic stability. Euchromatin and heterochromatin domains display major differences in histone modifications, biophysical properties, and spatiotemporal dynamics of DSB repair. However, it is unclear whether differential histone-modifying activities are required for DSB repair in these distinct domains. Here, we showed previously that the Drosophila melanogaster KDM4A (dKDM4A) histone demethylase is required for heterochromatic DSB mobility. Here we used locus-specific DSB induction in Drosophila animal tissues and cultured cells to more deeply interrogate the impact of dKDM4A on chromatin changes, temporal progression, and pathway utilization during DSB repair. We found that dKDM4A promotes the demethylation of heterochromatin-associated histone marks at DSBs in heterochromatin but not euchromatin. Most importantly, we demonstrate that dKDM4A is required to complete DSB repair in a timely manner and regulate the relative utilization of homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways but exclusively for heterochromatic DSBs. We conclude that the temporal kinetics and pathway utilization during heterochromatic DSB repair depend on dKDM4A-dependent demethylation of heterochromatic histone marks. Thus, distinct pre-existing chromatin states require specialized epigenetic alterations to ensure proper DSB repair.},
doi = {10.1101/gad.317537.118},
journal = {Genes & Development},
number = 1-2,
volume = 33,
place = {United States},
year = {Fri Dec 21 00:00:00 EST 2018},
month = {Fri Dec 21 00:00:00 EST 2018}
}
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