The emerging role of RNAs in DNA damage repair

Abstract

Many surveillance and repair mechanisms exist to maintain the integrity of our genome. All of the pathways described to date are controlled exclusively by proteins, which through their enzymatic activities identify breaks, propagate the damage signal, recruit further protein factors and ultimately resolve the break with little to no loss of genetic information. RNA is known to have an integral role in many cellular pathways, but, until very recently, was not considered to take part in the DNA repair process. Several reports demonstrated a conserved critical role for RNA-processing enzymes and RNA molecules in DNA repair, but the biogenesis of these damage-related RNAs and their mechanisms of action remain unknown. We will explore how these new findings challenge the idea of proteins being the sole participants in the response to DNA damage and reveal a new and exciting aspect of both DNA repair and RNA biology. Cell Death and Differentiation (2017) 24, 580-587; doi:10.1038/cdd.2017; published online 24 February 2017 FactsThe miRNA biogenesis machinery has a role in DNA damage repair outside of canonical miRNA-mediated translational repression. RNA molecules have been observed in the proximity of DNA breaks and have been implicated in the DNA repair response. These phenomena have been observed in many species, indicating an evolutionarily conserved mechanism. Open QuestionsWhat is the precise role of the RNA-processing enzymes in DNA repair? Do small RNAs have a direct mechanistic role in DNA repair, or do they serve as a by-product of a different RNA species? Is transcription induced locally at sites of DNA damage? Are proximal dormant promoter elements involved, or is an open-ended break sufficient for polymerase recruitment? Can these results be replicated outside of integrated exogenous reporter systems?An Unlikely Match: RNA Biogenesis Machinery Meets DNA Repair Our DNA is constantly exposed to various environmental and chemical agents, including ionising radiation (IR) from cosmic radiation, ultraviolet (UV) light from the sun or even nucleophilic attack induced by chemical compounds in food.1 In fact, DNA damage is intrinsic to the process of life: it is inevitable during replication and essential during meiotic recombination. Also, controlled DNA breaks by topoisomerase occur to facilitate the resolution of supercoiled chromatin structures.Complex mechanisms have evolved to counteract the variety and quantity of DNA damage encountered daily. Generally, DNA damage response (DDR) involves a complex signalling cascade initiated by one of three PI3K-like kinases: ATM, ATR or DNA-PK. They serve to facilitate chromatin modification and remodelling, allowing access to and acting as scaffolds for proteins involved in repair, as well as propagating the damage signal.1 Many of these recruited factors are involved in a binary decision-making process (see Figure 1). The repair of double-strand breaks (DSBs) is resolved by two distinct mechanisms: error-free homologous recombination (HR) or error-prone non-homologous ...

GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer

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“…However, a growing body of evidence suggests that RNA plays a significant role in the repair of DNA damage through currently unresolved mechanisms. [11][12][13][14][15][16][17][18] The emerging role of transcription, RNA-interacting proteins, RNA-processing enzymes, and RNA itself, in the repair of DNA damage is becoming increasingly apparent, [19][20][21][22] and understanding the contribution that RNA makes to the DDR will provide a new level of insight into genome maintenance. The concept of RNA-dependent DNA repair (RDDR) has the potential to alter our understanding of, and prospects for, cancer research and therapy, especially considering the recent emergence of RNA therapies.…”

Argonaute Proteins: From Structure to Function in Development and Pathological Cell Fate Determination

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