2009;28:2090C2099. mechanism underlying c-Myc down-regulation in response to UV-mediated DNA damage, wherein L11 promotes miR-130a-loaded miRISC to target mRNA. gene [3, 5, 6]. c-Myc translation can be regulated at both the 5-untranslated region (UTR) and the 3-UTR [7, 8]. c-Myc protein stability is subjected to a multitude of tight posttranslational regulation via the ubiquitin-dependent proteasome system [9C11]. Likewise, stability is regulated by a translation-independent mechanism including an AU-rich element (ARE) at its 3-UTR [12, 13] and a translation-dependent mechanism including an ~250 nucleotide (nt) coding region instability determinant (CRD) [14, 15]. Several ARE binding proteins, including AUF1 , HuR , and tristetraprolin (TPP)  have been found to bind ARE and act as mRNA destabilizing factors. CRD binding protein (CRD-BP) binds to the CRD, leading to the protection of mRNA from endoribonuclease cleavage within CRD [14, 15]. Finally, stability and/or translation are negatively regulated by several microRNAs (miRNAs), such as Let-7 , miR-145 , miR-34c , miR-24 [22, 23], and miR-185 . Together, c-Myc is usually precisely regulated to coordinate with normal cell growth and proliferation. c-Myc also needs to be tightly controlled under stress conditions. To overcome Bevirimat cellular stress and maintain genomic integrity, cells develop mechanisms to slow down cell cycle progression allowing cells to recover from your damage or eliminate the cells from your replicating Bevirimat pool if the damage is irreparable. One of the important mechanisms is usually p53-dependent cell cycle checkpoint that is activated by almost all kinds of stress, including DNA damage such as ultraviolet (UV) and -irradiation, oncogenic and ribosomal stress [25C27]. It has been shown that c-Myc overactivation can induce genomic instability [3, 28]. Thus, c-Myc needs to be tightly controlled in order to coordinate with stalled cell cycle progression in response to stress. Indeed, c-Myc protein is BGLAP reduced by treatment of cells with UV irradiation  and other DNA damaging brokers . However, the mechanisms underlying the c-Myc down-regulation in response to DNA damage are not completely comprehended. We previously found that ribosomal protein L11 (L11 thereafter) regulates c-Myc levels via miR-24-mediated mRNA decay in response to ribosomal stress . miRNAs are a class of Bevirimat small endogenous non-coding RNAs controlling the activity of ~50% of all protein-coding genes in mammals (33). Mature miRNAs are single stranded RNAs of ~23 nt in length that negatively regulate gene expression by base pairing to partially or perfectly complementary sites on the target mRNA, usually in the 3-UTR, to impact the translation and/or mRNA stability [31C33]. miRNAs play key functions in the regulation of diverse cellular processes ; deregulation of miRNAs is usually associated with the development of various human diseases including cancers [34C36]. L11 was initially found to be essential for p53 activation in response to ribosomal stress induced by perturbation of ribosomal biogenesis [37C39]. Ribosomal stress is usually often accompanied by the disruption of the nucleolus, leading to the relocation of the nucleolar components including ribosomal proteins into the nucleoplasm [40, 41]. Intriguingly, disruption of the nucleolus is also a common event in cells following DNA damage including UV irradiation , suggesting that L11 may play a role in regulating c-Myc via miRISC in response to DNA damage as well. In this study, we found that L11 recruits miR-130a-3p (miR-130a thereafter) to target mRNA following UV irradiation. Overexpression of miR-130a decreases both mRNA and protein and inhibits cell proliferation. UV damage induces the release of L11 from your nucleolus to the cytoplasm where it recruits miR-130a-associated RNA interference silencing complex (miRISC) to target mRNA at its 3-UTR. Thus our results uncover a novel function of miR-130a in suppressing c-Myc in response to DNA damage. RESULTS L11 associates with miR-130a We have previously shown that L11 associates with miR-24, but not other Myc-targeting miRNAs Bevirimat including let-7b and miR-34c, to repress c-Myc expression in response to Bevirimat ribosomal stress . To further elucidate the role of L11 in the regulation of c-Myc, we sought to examine whether it could associate with other miRNAs that negatively regulate cell growth and proliferation. We performed RNA-IP assays with anti-Flag antibody using lysates from.