title: MicroRNA-22 Suppresses DNA Repair and Promotes Genomic Instability through Targeting of MDC1.
abstract: MDC1 is critical component of the DNA damage response (DDR) machinery and orchestrates the ensuring assembly of the DDR protein at the DNA damage sites, and therefore loss of MDC1 results in genomic instability and tumorigenicity. However, the molecular mechanisms controlling MDC1 expression are currently unknown. Here, we show that miR-22 inhibits MDC1 translation via direct binding to its 3' untranslated region, leading to impaired DNA damage repair and genomic instability. We demonstrated that activated Akt1 and senescence hinder DDR function of MDC1 by upregulating endogenous miR-22. After overexpression of constitutively active Akt1, homologous recombination was inhibited by miR-22-mediated MDC1 repression. In addition, during replicative senescence and stress-induced premature senescence, MDC1 was downregulated by upregulating miR-22 and thereby accumulating DNA damage. Our results demonstrate a central role of miR-22 in the physiologic regulation of MDC1-dependent DDR and suggest a molecular mechanism for how aberrant Akt1 activation and senescence lead to increased genomic instability, fostering an environment that promotes tumorigenesis.
authors: DNA Damage Response Network Center, Chosun University School of Medicine, Gwangju, Republic of Korea. Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju, Republic of Korea. hjyou@chosun.ac.kr jhlee75@chosun.ac.kr jyong@umn.edu.
authors: Jung-Hee
authors: JH
authors: Lee
authors: DNA Damage Response Network Center, Chosun University School of Medicine, Gwangju, Republic of Korea. Division of Natural Medical Sciences, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors: Seon-Joo
authors: SJ
authors: Park
authors: DNA Damage Response Network Center, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors: Seo-Yeon
authors: SY
authors: Jeong
authors: DNA Damage Response Network Center, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors: Min-Ji
authors: MJ
authors: Kim
authors: DNA Damage Response Network Center, Chosun University School of Medicine, Gwangju, Republic of Korea. Department of Pharmacology, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors: Semo
authors: S
authors: Jun
authors: DNA Damage Response Network Center, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors: Hyun-Seo
authors: HS
authors: Lee
authors: DNA Damage Response Network Center, Chosun University School of Medicine, Gwangju, Republic of Korea. Department of Anatomy, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors: In-Youb
authors: IY
authors: Chang
authors: Department of Pathology, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors: Sung-Chul
authors: SC
authors: Lim
authors: Department of Anatomy, School of Medicine, Jeju National University, Jeju-Do, Republic of Korea.
authors: Sang Pil
authors: SP
authors: Yoon
authors: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, Minnesota. hjyou@chosun.ac.kr jhlee75@chosun.ac.kr jyong@umn.edu.
authors: Jeongsik
authors: J
authors: Yong
authors: DNA Damage Response Network Center, Chosun University School of Medicine, Gwangju, Republic of Korea. Department of Pharmacology, Chosun University School of Medicine, Gwangju, Republic of Korea. hjyou@chosun.ac.kr jhlee75@chosun.ac.kr jyong@umn.edu.
authors: Ho Jin
authors: HJ
authors: You
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000368:Aged; D000818:Animals; D018797:Cell Cycle Proteins; D016922:Cellular Senescence; D004249:DNA Damage; D004260:DNA Repair; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C413163:MDC1 protein, human; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D015534:Trans-Activators; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt