Hypoxia stabilizes SETDB1 to maintain genome stability-Reference-Cited by-全球学者库

Hypoxia stabilizes SETDB1 to maintain genome stability

Published:2023-10-18 Issue:20 Volume:51 Page:11178-11196
ISSN:0305-1048
Container-title:Nucleic Acids Research
language:en
Short-container-title:

Author:

Park Sungryul¹,Cho Jin Hwa¹,Kim Jong-Hwan²,Park Mijin³⁴,Park Seulki¹,Kim Seon-Young²⁴^ORCID,Kim Seon-Kyu³⁴,Kim Kidae⁵,Park Sung Goo¹⁴,Park Byoung Chul⁴⁶,Moon Jeong Hee⁷,Lee Gaseul⁷⁸^ORCID,Kim Sunhong⁹,Kim Jung-Ae¹³⁴^ORCID,Kim Jeong-Hoon¹⁴¹⁰

Affiliation:

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

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

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

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

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

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

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

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

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

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

Abstract

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.

Funder

National Research Foundation

Ministry of Science and ICT

Korea Research Institute of Bioscience and Biotechnology

Publisher

Oxford University Press (OUP)

Subject

Genetics

Link

https://academic.oup.com/nar/article-pdf/51/20/11178/53174902/gkad796.pdf

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