Data from MicroRNA-22 Suppresses DNA Repair and Promotes Genomic Instability through Targeting of MDC1
Year: 2023
Type: other
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. Cancer Res; 75(7); 1298–310. ©2015 AACR.
Authors: 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
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4361817137