A Reverse Transcriptase-Dependent Mechanism Plays Central Roles in Fundamental Biological Processes

Abstract

This review summarizes emerging evidence that LINE-1 (Long Interspersed Nuclear Elements) -encoded reverse transcriptase (RT) regulates fundamental biological processes. Earlier studies showed that sperm cells can be used as vectors of both exogenous DNA and RNA molecules in spermmediated gene transfer assays. During these studies, a sperm endogenous RT activity was identified, which can reverse-transcribe exogenous RNA directly, or DNA molecules through sequential transcription and reverse transcription. Resulting cDNA copies generated in sperm cells can be delivered to embryos at fertilization, further propagated in tissues as lowcopy extrachromosomal structures and transmitted to the progeny in a nonmendelian fashion. Being transcriptionally competent, they can induce phenotypic variations in positive tissues. An RT activity is also present in preimplantation embryos, and its inhibition causes developmental arrest in early preimplantation stages, paralleled by an extensive reprogramming of gene expression. In analogy with this, drug-mediated inhibition of RT activity, or RNA interference-mediated silencing of human LINE-1, reduce cell proliferation and induce differentiation in a variety of cancer cell lines. Furthermore, RT inhibition in vivo antagonizes the growth of human tumors in animal models. As a whole, these data implicate a RT-dependent machinery in the genesis of new genetic information in spermatozoa and in normal and pathological developmental processes.

LINEs of evidence: noncanonical DNA replication as an epigenetic determinant

“…These experiments have brought about very important but overlooked findings. Specifically, they demonstrate that the functional knockdown of L1 expression via L1-specific RNA interference (RNAi) and the inhibition of RT both independently result in the same biological outcomes [26,28]. This suggests that both transcription and reverse transcription of L1s are links in the same chain in these cell systems.…”

“…This suggests that numerous L1s may regulate transcription and DNA replication through their involvement in the establishment of the three-dimensional (3D) structure of chromatin. On the other hand, abundantly expressed FL-L1s are known to globally influence gene expression profiles, differentiation state, and proliferation capacity of early embryos and many types of cancer, although by mechanisms which remain unclear [26]. Thus far, the S/MAR-related function of L1s remains unexplored in conjunction with their expression status.…”

“…An important point in this regard is that the involvement of FL-L1 transcripts in the global regulation of early development and carcinogenesis seems to be mediated by L1 RT [26]. This raises the question as to whether substantial L1-related reverse transcription exists in early embryonic and cancer cell systems and, if so, what role it plays.…”

An alternative approach to medical genetics based on modern evolutionary biology. Part 2: retroviral symbiosis

“…Based on the fact that mature spermatozoa are endowed with reverse transcriptase, Spadafora and associates have blocked its action, using the anti-retroviral drug Nevirapine, to discover that this caused an irreversible arrest of development up to the four-cell stage of mouse development. 31 They further demonstrated that reverse transcriptase inhibition caused a substantial reprogramming of gene expression in arrested embryos, involving both developmental and translational genes. 32 This suggests that endogenous retroviruses, or LINE type products, are playing an important role at the earliest stages of mammalian development.…”

An alternative approach to medical genetics based on modern evolutionary biology. Part 4: HERVs in cancer

“…A fuller understanding of this HERV role, coupled with a deeper epigenetic understanding, is likely to contribute to new lines of therapy, including immunotherapy. 25,85 Part 5 of this series will examine the role of epigenetics and genomic duplications in health and disease. …”