DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and radio/chemo-sensitivity

doi:10.1038/s41388-022-02226-9

	DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and radio/chemo-sensitivity
	Chen, Bin 1,2,3; Xu, Feng 1,2,3; Gao, Yang 1,2,3; Hu, Guanshuo 1,2,3; Zhu, Kaili 1,2,3; Lu, Huayi 4; Xu, An 1,2; Chen, Shaopeng 1,2; Wu, Lijun 1,2,5; Zhao, Guoping 1,2
刊名	ONCOGENE
	2022-02-12
ISSN号	0950-9232
DOI	10.1038/s41388-022-02226-9
通讯作者	Zhao, Guoping(gpz@ipp.ac.cn)
英文摘要	HIGD1A is an important mitochondrial protein recently shown to have a novel nuclear localization under severe stress. However, whether this protein is also associated with the DNA damage response has rarely been studied. Here, we reported that DSBs-induced the translocation of mitochondrial HIGD1A to the nucleus is dependent on nuclear pore complex (NPCs), which finally promotes HR and radio/chemo-resistance. Importantly, NUP93 and HIGD1A physically interact and the interaction domain with NUP93 is located at residues 46-60 of HIGD1A. Chromatin-enriched HIGD1A can then directly interact with RPA. During the early stages of HR, HIGD1A promotes the loading of RPA to DSBs and activates the DNA damage-dependent chromatin association of RAD9-RAD1-HUS1 complex (9-1-1), which stimulates the ATR-Chk1-dependent G2/M DNA damage checkpoint. After facilitating RPA-ssDNA binding, HIGD1A in turn inhibits abnormal persistence of RPA1 foci by promoting ubiquitination of RPA1 and inducing its eventual proteasomal degradation. In addition, we have identified clinical drug Preveon associated with the HIGD1A-NUP93 interaction domain using a virtual screening approach. This compound directly interacted with HIGD1A, which was verified by NMR, and then inhibited HIGD1A translocation. Collectively, we demonstrate a novel role for HIGD1A in DSBs and provide rationale for using HIGD1A inhibitors as cancer therapeutics.
资助项目	National Science Fund for Excellent Young Scholars[12122510] ; National Natural Science Foundation of China[32171240] ; National Natural Science Foundation of China[11835014] ; National Natural Science Foundation of China[31870845] ; HFIPS Director's Fund[YZJJZX202014] ; CAS Pioneer Hundred Talents Program
WOS关键词	STRAND BREAK REPAIR ; PROTEIN-A RPA ; REPLICATION ; RAD51 ; IDENTIFICATION ; INHIBITORS ; DYNAMICS ; SITES ; SSDNA
WOS研究方向	Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
语种	英语
出版者	SPRINGERNATURE
WOS记录号	WOS:000754368500002
资助机构	National Science Fund for Excellent Young Scholars ; National Natural Science Foundation of China ; HFIPS Director's Fund ; CAS Pioneer Hundred Talents Program
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/127494]
专题	中国科学院合肥物质科学研究院
通讯作者	Zhao, Guoping
作者单位	1.Chinese Acad Sci, High Magnet Field Lab, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Anhui, Peoples R China 2.Chinese Acad Sci, Hefei Inst Phys Sci, Anhui Prov Key Lab Environm Toxicol & Pollut Cont, Hefei 230031, Anhui, Peoples R China 3.Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China 4.Univ Sci & Technol China, Affiliated Hosp 1, Div Life Sci & Med, USTC, Hefei 230001, Anhui, Peoples R China 5.Anhui Univ, Inst Phys Sci, Informat Mat & Intelligent Sensing Lab Anhui Prov, Hefei 230601, Anhui, Peoples R China
推荐引用方式 GB/T 7714	Chen, Bin,Xu, Feng,Gao, Yang,et al. DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and radio/chemo-sensitivity[J]. ONCOGENE,2022.
APA	Chen, Bin.,Xu, Feng.,Gao, Yang.,Hu, Guanshuo.,Zhu, Kaili.,...&Zhao, Guoping.(2022).DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and radio/chemo-sensitivity.ONCOGENE.
MLA	Chen, Bin,et al."DNA damage-induced translocation of mitochondrial factor HIGD1A into the nucleus regulates homologous recombination and radio/chemo-sensitivity".ONCOGENE (2022).