Abstract
The nucleolus has been known for a long time to fulfill crucial functions in ribosome biogenesis, of which cancer cells can become addicted to in order to produce sufficient amounts of proteins for cell proliferation. Recently, the nucleolus has emerged as a central regulatory hub in many other cancer-relevant processes, including stress sensing, DNA damage response, cell cycle control, and proteostasis. This fostered the idea that nucleolar processes can be exploited in cancer therapy. Interestingly, a significant proportion of poly(ADP-ribose) polymerase 1 (PARP1) molecules are localized in the nucleolus and PARP1 also plays crucial roles in many processes that are important in cancer biology, including genome maintenance, replication, transcription, and chromatin remodeling. Furthermore, during the last years, PARP1 came into focus in oncology since it represents a promising target of pharmacological PARP inhibitors in various types of cancers. Here, we provide an overview of our current understanding on the role of PARP1 in nucleolar functions and discuss potential implications in cancer biology and therapy.
Highlights
Introduction into the Biology of NucleoliNucleoli are self-organizing, membrane-less sub-compartments of the nucleus, which are formed around tandemly repeated clusters of 200 to 400 ribosomal DNA genes known as nucleolar organizing centers (NORs) on the short arms of the five human acrocentric chromosomes 13, 14, 15, 21, and 22 [1,2]
Consistent with the idea that such DNA damage-induced protein dynamics are regulated in a stress-specific manner, we recently found that after treatment with H2 O2 and the alkylating agent 2-chloroethyl ethyl sulfide (CEES), but not the topoisomerase inhibitor camptothecin (CPT), nucleolar-nucleoplasmic translocation of Werner protein (WRN) was dependent on the poly(ADP-ribose) polymerase 1 (PARP1) protein, yet independent of its enzymatic activity [69]
It is likely that pRNA stimulates PARP1 enzymatic activity, which is necessary to establish ribosomal DNA (rDNA) silencing. These findings indicate that PARP1 can modulate chromatin structure and gene expression in nucleoli, revealing a mechanism by which PARP1 ensures that silent rDNA
Summary
Nucleoli are self-organizing, membrane-less sub-compartments of the nucleus, which are formed around tandemly repeated clusters of 200 to 400 ribosomal DNA (rDNA) genes known as nucleolar organizing centers (NORs) on the short arms of the five human acrocentric chromosomes 13, 14, 15, 21, and 22 [1,2]. The main function of nucleoli is ribosome biogenesis, which is one of the most energy-demanding and highly controlled processes in a cell. RNA (pre-rRNA), which is rapidly processed by more than 200 non-ribosomal proteins and small nucleolar RNAs (snoRNAs) to mature 18S, 5.8S and 28S rRNAs [7]. Current evidence supports a model in which nucleoli are formed by a combination of active recruitment processes of proteins, active transcription of rDNA and formation of the respective rRNA, as well as phase separation processes involving both protein and RNA components [14]. The reassembly of nucleoli is initiated when pre-rRNA processing factors associate with NORs. First, multiple small nucleoli are formed, which as the cell cycle progresses coalesce to larger mature nucleoli [19]. PARylation and PARP1 (Section 3), and review the role of PARP1 in nucleolar functions (Section 4)
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