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Abstract
DNA damage response (DDR) is needed to repair damaged DNA for genomic integrity preservation. Defective DDR causes accumulation of deleterious mutations and DNA lesions that can lead to genomic instabilities and carcinogenesis. Identifying new players in the DDR, therefore, is essential to advance the understanding of the molecular mechanisms by which cells keep their genetic material intact. Here, we show that the core protein subunits Rpp29 and Rpp21 of human RNase P complex are implicated in DDR. We demonstrate that Rpp29 and Rpp21 depletion impairs double-strand break (DSB) repair by homology-directed repair (HDR), but has no deleterious effect on the integrity of non-homologous end joining. We also demonstrate that Rpp29 and Rpp21, but not Rpp14, Rpp25 and Rpp38, are rapidly and transiently recruited to laser-microirradiated sites. Rpp29 and Rpp21 bind poly ADP-ribose moieties and are recruited to DNA damage sites in a PARP1-dependent manner. Remarkably, depletion of the catalytic H1 RNA subunit diminishes their recruitment to laser-microirradiated regions. Moreover, RNase P activity is augmented after DNA damage in a PARP1-dependent manner. Altogether, our results describe a previously unrecognized function of the RNase P subunits, Rpp29 and Rpp21, in fine-tuning HDR of DSBs.
Highlights
The human genome is susceptible to endogenous and exogenous DNA damaging agents[1, 2]
Since phosphorylated RPA2 is a known indicator for ssDNA generation following DNA end resection, which promotes homology-directed repair (HDR) of DSB54, 55, these site-specific phosphorylation support the existence of persistent DNA 5′-end due to defective HDR of double-strand break (DSB)
We have shown that Rpp[29], Rpp[21] and H1 RNA are involved in DNA damage response (DDR)
Summary
The human genome is susceptible to endogenous and exogenous DNA damaging agents[1, 2]. DNA damage induces the expression of small and long ncRNAs, which regulate the recruitment of DDR proteins to chromatin and promote double-strand break (DSB) repair[19,20,21]. Human RNase P has non-canonical roles in regulating transcription of small ncRNA genes by RNA polymerase III (Pol III) and rRNA genes by RNA polymerase I (Pol I)[37, 48, 49]. Catalytic forms of this RNP exist in proficient initiation complexes assembled on target gene loci[50]. The aforementioned data prompted us to assess whether human RNase P has a role in DDR
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