Post-transcriptional regulation of LINE-1 retrotransposition by AID/APOBEC and ADAR deaminases

Abstract

Long interspersed element-1 (LINE-1 or L1) retrotransposons represent the only functional family of autonomous transposable elements in humans and formed 17% of our genome. Even though most of the human L1 sequences are inactive, a limited number of copies per individual retain the ability to mobilize by a process termed retrotransposition. The ongoing L1 retrotransposition may result in insertional mutagenesis that could lead to negative consequences such as genetic disease and cancer. For this reason, cells have evolved several mechanisms of defense to restrict L1 activity. Among them, a critical role for cellular deaminases [activation-induced deaminase (AID)/apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) and adenosine deaminases that act on RNA (ADAR) enzymes] has emerged. The majority of the AID/ APOBEC family of proteins are responsible for the deamination of cytosine to uracil (C-to-U editing) within DNA and RNA targets. The ADARs convert adenosine bases to inosines (A-to-I editing) within doublestranded RNA (dsRNA) targets. This review will discuss the current understanding of the regulation of LINE-1 retrotransposition mediated by these enzymes.

RNA Editors, Cofactors, and mRNA Targets: An Overview of the C-to-U RNA Editing Machinery and Its Implication in Human Disease

“…Other mammals have fewer (e.g., cats and cattle have three members, whereas mice have only one) [103]. The best-studied functions of the A3s are in innate immune responses to retroviruses and endogenous retroelements, although other types of viruses can also be inhibited by these proteins [104,105,106,107,108,109,110,111,112,113,114]. The burden of retroelements is believed to be responsible for the expansion of A3s from one member in mice, to seven in humans, leading to fewer active retroelements in humans, compared to mice [115,116].…”

Oocyte Quality Control: Causes, Mechanisms, and Consequences

“…piwi-interacting small RNA ( piRNA) biogenesis is a particularly important mechanism for silencing transposable elements, including L1, in the germline and is also required for their de novo remethylation (Aravin et al 2008;Kuramochi-Miyagawa et al 2008;Castañeda et al 2011). Posttranscriptionally, RNA interference, degradation, premature polyadenylation, and editing can attenuate LINE-1 activity (Perepelitsa- Belancio and Deininger 2003;Yang and Kazazian 2006;Schumann 2007;Zhang et al 2014;Hamdorf et al 2015;Orecchini et al 2018).…”

APOBEC3B Activity Is Prevalent in Urothelial Carcinoma Cells and Only Slightly Affected by LINE-1 Expression

“…It is assumed that retroelements, including endogenous retroviruses that are flanked by long terminal repeats (LTRs), and non-LTR retrotransposons such as long interspersed nuclear element-1 (LINE-1, L1) and short interspersed nuclear elements (SINEs), have been the original targets of A3 activity and have provided the evolutionary pressure necessary for the continuous expansion of the A3 locus in primates ( Münk et al, 2012 ). Mobilization of these retroelements is restricted by the different members of the A3 protein family to protect the genome from deleterious retrotransposition events ( Muckenfuss et al, 2006 ; Schumann, 2007 ; Chiu and Greene, 2008 ; Goodier and Kazazian, 2008 ; Horn et al, 2013 ; Orecchini et al, 2018 ). For instance, the role of A3B in intracellular defense against transposable element activity was recently demonstrated by a twofold to fourfold increase in retrotransposition efficiency of an engineered human L1 reporter after shRNA-based knockdown of A3B in hESCs ( Wissing et al, 2011 ).…”