DICER and ZRF1 contribute to chromatin decondensation during nucleotide excision repair

Abstract

Repair of damaged DNA relies on the recruitment of DNA repair factors in a well orchestrated manner. As a prerequisite, the chromatin needs to be decondensed by chromatin remodelers to allow for binding of repair factors and for DNA repair to occur. Recent studies have implicated members of the SWI/SNF and INO80 families as well as PARP1 in nucleotide excision repair (NER). In this study, we report that the endonuclease DICER is implicated in chromatin decondensation during NER. In response to UV irradiation, DICER is recruited to chromatin in a ZRF1-mediated manner. The H2A–ubiquitin binding protein ZRF1 and DICER together impact on the chromatin conformation via PARP1. Moreover, DICER-mediated chromatin decondensation is independent of its catalytic activity. Taken together, we describe a novel function of DICER at chromatin and its interaction with the ubiquitin signalling cascade during GG-NER.

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“…However, the primary mode of action of DICER appears to involve the assembly of chromatin remodelling complexes. PARP1 inhibitors as well as a knockdown of PARP1 entirely abolish DICERdependent chromatin decondensation further supporting this premise [5]. DICER contains a PAZ domain at its c-terminus, which interacts with PIWI, Argonaut and Zwille.…”

“…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.…”

“…Depletion of ZRF1 causes abnormal differentiation and impairs formation of all three germ layers during embryonic development. Given the robust interaction of DICER with ZRF1 [5], DICER, apart from its cytoplasmic function in conjunction with the RISC complex, might turn out to be a master regulator of chromatin conformation during cellular differentiation. Likewise, DNA replication is accompanied by H2A-ubiquitylation, which could constitute another example for ZRF1-DICER facilitated chromatin decondensation.…”

“…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.…”

“…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.…”