RNA ligases play an important role in RNA repair, thereby maintaining RNA integrity. Any malfunction in RNA repair in хората seems to be associated with diseases like neurodegeneration and cancer. Discovery of a novel човешки протеин (C12orf29 on chromosome 12) as an RNA ligase, therefore, has relevance in development of novel treatments for such diseases. Researchers have proposed to name this протеин as Homo sapiens RNA ligase (HsRnl).
Лигазата е ензим който катализира свързването или лигирането на две молекули нуклеинова киселина обикновено чрез хидролиза. Например, ДНК лигазата улеснява свързването на ДНК strands by catalysing formation of phosphodiester bond thereby playing a key role maintaining genome integrity during the process of DNA replication, recombination and repair throughout the life span of the organism. Similarly, РНК ligase catalyses the formation of phosphodiester bonds between 3′-OH and 5′-P groups of РНК molecules. It, therefore, plays a key role in РНК repair and maintaining cellular fitness.
- откритие of C12orf29 happened while identifying AMPylated (Adenosine Mono Phosphorylated) протеини via chemical proteomics approach1. AMPylation involves covalent attachment of AMP to протеин side chains via phosphodiester bonds in which ATP acts as a co-substrate. The протеин is 37 kDa in size and consists of 325 amino acids. Surprisingly, it is highly conserved in higher еукариоти but absent in lower еукариоти such as yeast. Functional analysis showed that it possessed 5’-3’ РНК ligase activity. Mutational analysis revealed that changes in certain residues referring to mutations D59N, R77L, E123D, and K263N were found in patients suffering from esophageal squamous cell carcinoma, glioblastoma, chronic lymphocytic leukemia, and ovarian serous cystadenocarcinoma respectively. All the above 3 mutations except E123D lead to impaired РНК лигиране.
Knock out of C12orf29 in HEK293 (човешки embryonic kidney) cells leads to vulnerability of cells towards reactive oxygen species suggesting that this протеин plays an important role in repairing damaged РНК caused by the generation of reactive oxygen species1. Identification of this novel протеин, на име HsRnl (Хомо сапиенс РНК ligase), has several implications in the development of novel therapeutics as impairment of РНК repair in хората is associated with the onset of several diseases such as neurodegeneration and отказr2, 3.
***
Литература:
- Yuan Y., et al 2022. A човешки РНК ligase that operates via auto- and РНК-AMPylation. bioRxiv preprint. Posted 19 August 2022. DOI: https://doi.org/10.1101/2022.07.18.500566
- Burroughs A. M. & Aravind L. RNA damage in biological conflicts and the diversity of responding РНК repair systems. Nucleic Acids Res. 44, 8525-8555 (2016). https://doi.org/10.1093/nar/gkw722
- Yan, L. L. & Zahner, H. S. How do cells cope with РНК damage and its consequences? J. Biol. Chem. 294, 15158-15171 (2019). DOI: https://doi.org/10.1074/jbc.REV119.006513
***
