ADAR-mediated RNA editing of KRAB-ZFPs act as a diversifier, in the defense against endogenous retroelements

Nearly half of the human genome consists of endogenous retroelements (EREs). Unrestricted propagation of EREs by duplications can severely damage the genome integrity, undermining cell and organism survival. The Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) recognize and bind to EREs` specific DNA sequence, thus repressing the EREs transcription by recruiting histone deacetylases and methylase to condense chromatin. The DNA-protein specificity is determined by specific amino residues in the C2H2 binding domain of KRAB-ZFPs proteins. Mutations in ERE DNA sequence can allow the ERE to escape recognition by the KRAB-ZFP and reproduce without regulation in the host`s genome. RNA Editing by adenosine deaminase acting on RNA (ADAR) converts adenosines to inosines (A→I) altering the sequence of RNA transcripts from that encoded in the genome. Here, we propose that A-to-I RNA editing in the KRAB-ZFP amino acids sequence can insert a corresponding change, recover the mutated ERE recognition and restore the previous steady state. Different combinations of `n` unique editing sites in a KRAB-ZFP transcripts can enable up to 2ⁿ binding DNA sequences for one gene. Our preliminary results show significant enrichment in A-to-I editing at bind-determine sites of KRAB-ZFP in embryonic stem cells; This leads up to 2²⁷ binding sequences for ZNF91 and significant numbers in other genes in the family. This finding suggests that A-to-I RNA editing in KRAB-ZFP may be a mechanism for creating diverse immune system against endogenous retroelements by creating a vast KRAB-ZFP repertoire with the ability to protect against wide genome threats.