MicroRNA-22 suppresses DNA repair and promotes genomic instability through targeting of MDC1

Jung Hee Lee, Seon Joo Park, Seo Yeon Jeong, Min Ji Kim, Semo Jun, Hyun Seo Lee, In Youb Chang, Sung Chul Lim, Sang Pil Yoon, Jeongsik Yong, Ho Jin You

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1298-1310
Number of pages13
JournalCancer Research
Issue number7
StatePublished - Apr 1 2015

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©2015 AACR.


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