Untitled

Abstract

The accessibility of chromatin is an essential feature of DNA templated processes such as DNA replication, transcription and DNA repair. The chromatin condensation state, and thus accessibility, is modulated by a variety of chromatin remodeling complexes [1] as well as epigenetic components; for instance by bridging gene regulatory elements [2]. More recently, the function of ncRNAs in regulating chromatin has received much attention. One important player that processes ncRNAs to control gene expression in the cytoplasm and nucleus is the endoribonuclease DICER. DICER cleaves doublestranded RNA into short double-stranded RNA fragments called small interfering RNAs (siRNA) and microRNA (miRNA). Whereas miRNAs are essential to degrade mRNAs in the cytoplasm, siRNAs produced by DICER contribute to the generation of heterochromatin [3] (Figure 1). RNA generated from the locus to be silenced is converted into dsRNA by the activity of RNA dependent RNA polymerase (RDRP), and the resulting dsRNA is subsequently processed by DICER (Figure 1). siRNAs generated by DICER are loaded into the RITS (RNAinduced transcriptional silencing) complex, which targets the RITS complex to chromatin causing the spreading of H3K9-trimethylation along the chromatin fiber [3]. Likewise, DICER contributes to the DNA damage response by generating small non-coding RNAs at DNA double strand breaks that are necessary for the recruitment of the mediators MDC1 and 53BP1 [4].Very recently a novel function of DICER was identified that contrasts its conventional RNA-dependent functions in regulating chromatin conformation [5]. Contrary to its role in forming heterochromatin in a siRNA dependent fashion, DICER also facilitates the decondensation of chromatin at DNA damage sites. Importantly, this novel and unexpected role was demonstrated to be independent of its catalytic activity. DICER is recruited to chromatin by the H2A-ubiquitin binding protein ZRF1, which links DICER not only to the ubiquitin signaling pathways during DNA repair but potentially also to the ZRF1-dependent activation of genes during stem cell differentiation. ZRF1 associates to chromatin by tethering to the epigenetic H2A-ubiquitin mark and by binding RNA with its c-terminal SANT domains [6] (Figure 1). ZRF1 may be regarded a tethering platform for DICER, the Poly [ADP-ribose] polymerase 1 (PARP1) and SWI/SNF chromatin remodelling complexes [5], which contribute to the decondensation of chromatin structures. Hence, DICER represents a general tool to shape the chromatin conformation. Employing its siRNA processing activity it contributes to chromatin condensation, while in complex with ZRF1 and chromatin remodeling factors and independent of its catalytic activity it contributes to chromatin decondensation (Figure 1). An important question remaining is how DICER carries out these different functions and in particular how it can facilitate chromatin decondensation. Regulating the EditorialFigure 1: Regulating chromatin conformation: The two faces of DICER. DICER facilitates chroma...

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