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Heat-Induced SIRT1-Mediated H4K16ac Deacetylation Impairs Resection and SMARCAD1 Recruitment to Double Strand Breaks

63 Pages Posted: 12 Jan 2022 Publication Status: Published

See all articles by Sharmistha Chakraborty

Sharmistha Chakraborty

Houston Methodist Research Institute

Mayank Singh

affiliation not provided to SSRN

Raj Pandita

affiliation not provided to SSRN

Vipin Singh

affiliation not provided to SSRN

Calvin Lo

affiliation not provided to SSRN

Fransisca Leonard

Houston Methodist Research Institute

Nobuo Horikoshi

affiliation not provided to SSRN

Eduardo Moros

affiliation not provided to SSRN

Deblina Guha

affiliation not provided to SSRN

Clayton Hunt

affiliation not provided to SSRN

Kaplana Makhijani

University of Florida

Eric Chau

affiliation not provided to SSRN

Kazi Ahmed

affiliation not provided to SSRN

Prayas Sethi

All India Institute of Medical Sciences (AIIMS) - Department of Medicine

Vijay Charaka

affiliation not provided to SSRN

Biana Godin

affiliation not provided to SSRN

Kalpana Makhijani

affiliation not provided to SSRN

Harry Scherthan

affiliation not provided to SSRN

Jeanette Deck

affiliation not provided to SSRN

Michael Hausmann

affiliation not provided to SSRN

Arjamand Mushtaq

affiliation not provided to SSRN

Mohmmad Altaf

University of Kashmir

Kenneth Ramos

Texas A&M University

Krishna Bhat

affiliation not provided to SSRN

Nitika Taneja

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics

Chandrima Das

affiliation not provided to SSRN

Tej Pandita

Texas A&M University

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Abstract

Heat stroke deaths are prevalent in tropical regions of the globe. Hyperthermia inhibits DNA double strand break (DSB) repair by homologous recombination (HR) pathway, however, the mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential for genomic stability and transcription. Heat-induced reduction in H4K16ac were detectable in humans, Drosophila and yeast, suggesting that this is a highly conserved response. We examined the recruitment of several histone deacetylases to chromatin after heat-shock and discovered mainly SIRT1 enrichment to gene-rich regions. Recruitment of SIRT1 upon heat-shock is impacted by SMARCAD1 depletion in an antagonistic manner. Like hyperthermia, SMARCAD1 depletion and a combination of the two, impaired 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 mechanism whereby hyperthermia-induced H4K16ac deacetylation impacts chromatin organization, negatively impacting DSB repair.

Keywords: H4K16ac, SIRT1, MOF, SMARCAD1, heat-shock, DSB repair, replication stress, active replication fork stability, gene rich region

Suggested Citation

Chakraborty, Sharmistha and Singh, Mayank and Pandita, Raj and Singh, Vipin and Lo, Calvin and Leonard, Fransisca and Horikoshi, Nobuo and Moros, Eduardo and Guha, Deblina and Hunt, Clayton and Makhijani, Kaplana and Chau, Eric and Ahmed, Kazi and Sethi, Prayas and Charaka, Vijay and Godin, Biana and Makhijani, Kalpana and Scherthan, Harry and Deck, Jeanette and Hausmann, Michael and Mushtaq, Arjamand and Altaf, Mohmmad and Ramos, Kenneth and Bhat, Krishna and Taneja, Nitika and Das, Chandrima and Pandita, Tej, Heat-Induced SIRT1-Mediated H4K16ac Deacetylation Impairs Resection and SMARCAD1 Recruitment to Double Strand Breaks. Available at SSRN: https://ssrn.com/abstract=4007582 or http://dx.doi.org/10.2139/ssrn.4007582
This version of the paper has not been formally peer reviewed.

Sharmistha Chakraborty

Houston Methodist Research Institute ( email )

6670 Bertner Ave
Houston, 77030
United States

Mayank Singh

affiliation not provided to SSRN ( email )

No Address Available

Raj Pandita

affiliation not provided to SSRN ( email )

No Address Available

Vipin Singh

affiliation not provided to SSRN ( email )

No Address Available

Calvin Lo

affiliation not provided to SSRN ( email )

No Address Available

Fransisca Leonard

Houston Methodist Research Institute ( email )

6670 Bertner Ave
Houston, 77030
United States

Nobuo Horikoshi

affiliation not provided to SSRN ( email )

No Address Available

Eduardo Moros

affiliation not provided to SSRN ( email )

No Address Available

Deblina Guha

affiliation not provided to SSRN ( email )

No Address Available

Clayton Hunt

affiliation not provided to SSRN ( email )

No Address Available

Kaplana Makhijani

University of Florida ( email )

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Eric Chau

affiliation not provided to SSRN ( email )

No Address Available

Kazi Ahmed

affiliation not provided to SSRN ( email )

No Address Available

Prayas Sethi

All India Institute of Medical Sciences (AIIMS) - Department of Medicine ( email )

New Delhi
India

Vijay Charaka

affiliation not provided to SSRN ( email )

No Address Available

Biana Godin

affiliation not provided to SSRN ( email )

No Address Available

Kalpana Makhijani

affiliation not provided to SSRN

Harry Scherthan

affiliation not provided to SSRN ( email )

No Address Available

Jeanette Deck

affiliation not provided to SSRN ( email )

No Address Available

Michael Hausmann

affiliation not provided to SSRN ( email )

No Address Available

Arjamand Mushtaq

affiliation not provided to SSRN

Mohmmad Altaf

University of Kashmir ( email )

Srinagar
University of Kashmir
Srinagar, 190006
India

Kenneth Ramos

Texas A&M University ( email )

Krishna Bhat

affiliation not provided to SSRN ( email )

No Address Available

Nitika Taneja

Erasmus University Rotterdam (EUR) - Department of Molecular Genetics ( email )

Rotterdam
Netherlands

Chandrima Das

affiliation not provided to SSRN ( email )

No Address Available

Tej Pandita (Contact Author)

Texas A&M University ( email )

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