Regulatory mechanisms of RNA function: emerging roles of DNA repair enzymes

Abstract

The acquisition of an appropriate set of chemical modifications is required in order to establish correct structure of RNA molecules, and essential for their function. Modification of RNA bases affects RNA maturation, RNA processing, RNA quality control, and protein translation. Some RNA modifications are directly involved in the regulation of these processes. RNA epigenetics is emerging as a mechanism to achieve dynamic regulation of RNA function. Other modifications may prevent or be a signal for degradation. All types of RNA species are subject to processing or degradation, and numerous cellular mechanisms are involved. Unexpectedly, several studies during the last decade have established a connection between DNA and RNA surveillance mechanisms in eukaryotes. Several proteins that respond to DNA damage, either to process or to signal the presence of damaged DNA, have been shown to participate in RNA quality control, turnover or processing. Some enzymes that repair DNA damage may also process modified RNA substrates. In this review, we give an overview of the DNA repair proteins that function in RNA metabolism. We also discuss the roles of two base excision repair enzymes, SMUG1 and APE1, in RNA quality control.

Quality control of chemically damaged RNA

“…Interestingly, the 25S NRD factors Mms1p and Rtt101p are involved in DNA repair [79] and are sensitive to nucleic acid damaging agents [80], suggesting an overlap between RNA and DNA quality control processes. Indeed, recent reports have also implicated a number of base excision repair (BER) factors in RNA quality control, especially during ribosome biogenesis (for review see [81]). For example, the main eukaryotic apurinic/apyrimidinic endonuclease APE1, which is responsible for creating a nick in DNA at abasic sites, has an endonucleolytic activity on abasic RNA as well as different types of damaged RNA [82].…”

Dual roles of DNA repair enzymes in RNA biology/post‐transcriptional control

“…In addition, in response to stress PARP1 modifies poly(A) polymerase (PAP), leading to globally reduced 3′‐mRNA end processing, inhibition of mRNA synthesis, and its export to the cytoplasm . PARP1 is also involved in the formation of Cajal bodies and has been proposed to contribute to protein shuttling from the nucleolus to the Cajal body, which impacts on RNA processing within these bodies . Consistent with this, depletion of PARP1 leads to accumulation of rRNA intermediates in the nucleolus and nucleolar disintegration, indicating that PARP1 seems to regulate rRNA processing and ribosome assembly .…”

“…In contrast, long‐patch BER involves the binding of RPA to single‐stranded regions of DNA and the subsequent recruitment of the DNA replication machinery, resulting in replication‐based replacement of missing bases along with displacement and replacement of a number of downstream bases leading to the formation of a single‐stranded DNA (ssDNA) ‘flap’ downstream of the damage site. Flap endonuclease‐1 (FEN1) then cleaves the displaced ssDNA flap and the remaining DNA nick is sealed by DNA ligase 1 …”

“…Several other BER proteins have also been implicated in RNA metabolism. For example, the OGG1 and NEIL2 DNA glycosylases, XRCC1, as well as FEN1 accumulate in the nucleolus (Figure ), where OGG1 shuttling seems to be dependent on rDNA transcription lead by polymerase I . Additionally, FEN1, a member of the long‐patch BER subpathway, has been demonstrated to cleave RNA at 5′ stem structures in vitro (Figure ).…”

“…Flap endonuclease-1 (FEN1) then cleaves the displaced ssDNA flap and the remaining DNA nick is sealed by DNA ligase 1. 67 Of late, roles for many members of the BER pathway have been proposed within RNA processing mechanisms, the most well-characterized examples including APE1, PARP1, and the SMUG1 (singlestrand selective monofunctional uracil DNA glycosylase 1) glycosylase.…”