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Nucleic Acids Res., Oct 18 2023, gkad796 | https://doi.org/10.1093/nar/gkad796 Hypoxia stabilizes SETDB1 to maintain genome stability

Sungryul Park ¹, Jin Hwa Cho ¹, Jong-Hwan Kim², Mijin Park ^3,4, Seulki Park ¹, Seon-Young Kim ^2,4, Seon-Kyu Kim ^3,4, Kidae Kim⁵, Sung Goo Park ^1,4, Byoung Chul Park ^4,6, Jeong Hee Moon ⁷, Gaseul Lee ^7,8, Sunhong Kim ⁹, Jung-Ae Kim^1,3,4,* Jeong-Hoon Kim ^1,4,10*

¹Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.

²Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.

³Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.

⁴Department of Bioscience, University of Science and Technology, Daejeon 34113, Republic of Korea.

⁵R&D Center, PharmAbcine Inc., Daejeon 34047, Republic of Korea.

⁶Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.

⁷Core Research Facility & Analysis Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.

⁸College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea.

⁹Drug Discovery Center, LG Chem Ltd., Seoul 07796, Republic of Korea.

¹⁰Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.

^*To whom correspondence should be addressed. : Jung-Ae Kim

Correspondence may also be addressed to Jeong-Hoon Kim.

Abstract

Von Hippel-Lindau (VHL) is a tumor suppressor that functions as the substrate recognition subunit of the CRL2VHL E3 complex. While substrates of VHL have been identified, its tumor suppressive role remains to be fully understood. For further determination of VHL substrates, we analyzed the physical interactome of VHL and identified the histone H3K9 methyltransferase SETBD1 as a novel target. SETDB1 undergoes oxygen-dependent hydroxylation by prolyl hydroxylase domain proteins and the CRL2VHL complex recognizes hydroxylated SETDB1 for ubiquitin-mediated degradation. Under hypoxic conditions, SETDB1 accumulates by escaping CRL2VHL activity. Loss of SETDB1 in hypoxia compared with that in normoxia escalates the production of transposable element-derived double-stranded RNAs, thereby hyperactivating the immune-inflammatory response. In addition, strong derepression of TEs in hypoxic cells lacking SETDB1 triggers DNA damage-induced death. Our collective results support a molecular mechanism of oxygen-dependent SETDB1 degradation by the CRL2VHL E3 complex and reveal a role of SETDB1 in genome stability under hypoxia.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-10-23)
연구진국내 연구진
분야 생명과학 > 세포생물학

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