DNA repair by RNA: Templated, or not templated, that is the question

Abstract

Cells are continuously exposed to both endogenous and exogenous sources of genomic stress. To maintain chromosome stability, a variety of mechanisms have evolved to cope with the multitude of genetic abnormalities that can arise over the life of a cell. Still, failures to repair these lesions are the driving force of cancers and other degenerative disorders. DNA double-strand breaks (DSBs) are among the most toxic genetic lesions, inhibiting cell ability to replicate, and are sites of mutations and chromosomal rearrangements. DSB repair is known to proceed via two major mechanisms: homologous recombination (HR) and non-homologous end joining (NHEJ). HR reliance on the exchange of genetic information between two identical or nearly identical DNA molecules offers increased accuracy. While the preferred substrate for HR in mitotic cells is the sister chromatid, this is limited to the S and G2 phases of the cell cycle. However, abundant amounts of homologous genetic substrate may exist throughout the cell cycle in the form of RNA. Considered an uncommon occurrence, the direct transfer of information from RNA to DNA is thought to be limited to special circumstances. Studies have shown that RNA molecules reverse transcribed into cDNA can be incorporated into DNA at DSB sites via a non-templated mechanism by NHEJ or a templated mechanism by HR. In addition, synthetic RNA molecules can directly template the repair of DSBs in yeast and human cells via an HR mechanism. New work suggests that even endogenous transcript RNA can serve as a homologous template to repair a DSB in chromosomal DNA. In this perspective, we will review and discuss the recent advancements in DSB repair by RNA via non-templated and templated mechanisms. We will provide current findings, models and future challenges investigating RNA and its role in DSB repair.

DEAD Box 1 Facilitates Removal of RNA and Homologous Recombination at DNA Double-Strand Breaks

“…However, recent evidence suggests that novel DSB repair pathways involving RNA templates may be functional throughout the cell cycle, including G 1 . RNA template-guided DSB repair has been reported in both mammalian cells and bacteria and involves RNA molecules that serve as templates to guide DNA synthesis during DSB repair (72)(73)(74)(75)(76). Regulation of RNA-DNA duplexes, including both their formation and resolution, may be critical to this repair process.…”

Telomeric Double Strand Breaks Facilitate Formation of 5’ C-Rich Overhangs in G1 Human Cells

“…Importantly however, RNA-templated DSB repair has recently been reported in human cells, a pathway that would be resection dependent and potentially not mediated by other conventional repair factors (70,71). Our finding of telomeric RNA TERRA-bound 5' C-rich (ss)telomeric DNA at telomeric DSB break sites in human ALT cells is particularly relevant in this regard.…”

RNA nanoparticles harboring annexin A2 aptamer can target ovarian cancer for tumor-specific doxorubicin delivery

“…Liposomes are known to accumulate in the liver, and the drug-loaded liposomes can cause significant liver toxicity 42 . Nucleic acids, beyond the native function for RNA interference 43–45 , enzyme-like activity 46 , DNA repair 47 , and other genome editing 48 , can also be designed and constructed with defined shape and structure 49,50 . Nucleic acid nanoparticles have great potential to overcome the liver accumulation limitations for in vivo application 23,24,27,28,31,51 , with the nature of negative surface charge and well defined particle shape and size.…”