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

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; Tej K Pandita

doi:10.1016/j.isci.2022.104142

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

iScience. 2022 Mar 23;25(4):104142. doi: 10.1016/j.isci.2022.104142. eCollection 2022 Apr 15.

Authors

Sharmistha Chakraborty^{1

2}, Mayank Singh^{2

3}, Raj K Pandita^{1

2

4

5}, Vipin Singh^{6

7}, Calvin S C Lo⁸, Fransisca Leonard¹, Nobuo Horikoshi^{1

2

5}, Eduardo G Moros^{5

9}, Deblina Guha⁶, Clayton R Hunt^{1

2

5}, Eric Chau¹, Kazi M Ahmed¹, Prayas Sethi³, Vijaya Charaka¹, Biana Godin¹, Kalpana Makhijani¹⁰, Harry Scherthan¹¹, Jeanette Deck¹², Michael Hausmann¹², Arjamand Mushtaq¹³, Mohammad Altaf¹³, Kenneth S Ramos¹⁴, Krishna M Bhat¹⁰, Nitika Taneja⁸, Chandrima Das^{6

7}, Tej K Pandita^{1

2

4

5

14}

Affiliations

¹ Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA.
² Department of Radiation Oncology, University of Texas Southwestern Medical Centre, Dallas, TX, USA.
³ Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi 110029, India.
⁴ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Departments of Radiation Oncology, Washington University, St Louis, MO, USA.
⁶ Biophysics & Structural Genomics Division Saha Institute of Nuclear Physics, Bidhan Nagar, Kolkata, West Bengal 700064, India.
⁷ Homi Bhaba National Institute, Mumbai, India.
⁸ Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 Rotterdam, CA, the Netherlands.
⁹ Departments of Radiation Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
¹⁰ Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA.
¹¹ Bundeswehr Institute of Radiobiology Affiliated to the University of Ulm, Neuherbergstr. 11, 80937 Munich, Germany.
¹² Kirchhoff-Institute for Physics, Heidelberg University, Im Neuenheimer Feld 227, 69120 Heidelberg, Germany.
¹³ Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir 190006, India.
¹⁴ Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX, USA.

Abstract

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.

Keywords: Biological sciences; Epigenetics; Molecular biology.

Abstract

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