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Heat-induced SIRT1-mediated H4K16ac deacetylation impairs resection and SMARCAD1 recruitment to double strand breaks

Hyperthermia inhibits DNA double-strand break (DSB) repair that utilizes homologous recombination (HR) pathway by a poorly defined mechanism(s); however, the mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modificat...

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Main Authors: Chakraborty, Sharmistha (Author) , Singh, Mayank (Author) , Pandita, Raj K. (Author) , Singh, Vipin (Author) , Lo, Calvin S. C. (Author) , Leonard, Fransisca (Author) , Horikoshi, Nobuo (Author) , Moros, Eduardo G. (Author) , Guha, Deblina (Author) , Hunt, Clayton R. (Author) , Chau, Eric (Author) , Ahmed, Kazi M. (Author) , Sethi, Prayas (Author) , Charaka, Vijaya (Author) , Godin, Biana (Author) , Makhijani, Kalpana (Author) , Scherthan, Harry (Author) , Deck, Jeanette (Author) , Hausmann, Michael (Author) , Mushtaq, Arjamand (Author) , Altaf, Mohammad (Author) , Ramos, Kenneth S. (Author) , Bhat, Krishna M. (Author) , Taneja, Nitika (Author) , Das, Chandrima (Author) , Pandita, Tej K. (Author)
Format: Article (Journal)
Language:English
Published: 7 April 2022
In: iScience
Year: 2022, Volume: 25, Issue: 4, Pages: 1-24
ISSN:2589-0042
DOI:10.1016/j.isci.2022.104142
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.isci.2022.104142
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S2589004222004126
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Author Notes:Sharmistha Chakraborty, Mayank Singh, Raj K. Pandita, Vipin Singh, Calvin S.C. Lo, Fransisca Leonard, Nobuo Horikoshi, Eduardo G. Moros, Deblina Guha, Clayton R. Hunt, Eric Chau, Kazi M. Ahmed, Prayas Sethi, Vijaya Charaka, Biana Godin, Kalpana Makhijani, Harry Scherthan, Jeanette Deck, Michael Hausmann, Arjamand Mushtaq, Mohammad Altaf, Kenneth S. Ramos, Krishna M. Bhat, Nitika Taneja, Chandrima Das, and Tej K. Pandita
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Summary:Hyperthermia inhibits DNA double-strand break (DSB) repair that utilizes homologous recombination (HR) pathway by a poorly defined mechanism(s); however, the mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential for genome stability and transcription. Heat-induced reduction in H4K16ac was detected in humans, Drosophila, and yeast, indicating that this is a highly conserved response. The examination of histone deacetylase recruitment to chromatin after heat-shock identified SIRT1 as the major deacetylase subsequently enriched at gene-rich regions. Heat-induced SIRT1 recruitment was antagonized by chromatin remodeler SMARCAD1 depletion and, like hyperthermia, the depletion of the SMARCAD1 or combination of the two impaired DNA end resection and increased replication stress. Altered repair protein recruitment was associated with heat-shock-induced γ-H2AX chromatin changes and DSB repair processing. These results support a novel mechanism whereby hyperthermia impacts chromatin organization owing to H4K16ac deacetylation, negatively affecting the HR-dependent DSB repair.
Item Description:Gesehen am 08.08.2022
Physical Description:Online Resource
ISSN:2589-0042
DOI:10.1016/j.isci.2022.104142

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