ISSN 0006-2979, Biochemistry (Moscow), 2023, Vol. 88, No. 11, pp. 1754-1762 © The Author(s) 2023. This article is an open access publication.
Published in Russian in Biokhimiya, 2023, Vol. 88, No. 11, pp. 2127-2137.
175 4
REVIEW
To Be Mobile or Not:
The Variety of Reverse Transcriptases
and Their Recruitment by Host Genomes
Irina R. Arkhipova
1,a
* and Irina A. Yushenova
1,b
1
Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory,
Woods Hole, MA 02543, USA
a
e-mail: iarkhipova@mbl.edu
b
e-mail: iyushenova@mbl.edu
Received September 13, 2023
Revised September 18, 2023
Accepted September 20, 2023
Abstract— Reverse transcriptases (RT), or RNA-dependent DNA polymerases, are unorthodox enzymes that originally
added a new angle to the conventional view of the unidirectional flow of genetic information in the cell from DNA to
RNA to protein. First discovered in vertebrate retroviruses, RTs were since re-discovered in most eukaryotes, bacteria,
and archaea, spanning essentially all domains of life. For retroviruses, RTs provide the ability to copy the RNA genome
into DNA for subsequent incorporation into the host genome, which is essential for their replication and survival. In cel-
lular organisms, most RT sequences originate from retrotransposons, the type of self-replicating genetic elements that rely
on reverse transcription to copy and paste their sequences into new genomic locations. Some retroelements, however, can
undergo domestication, eventually becoming a valuable addition to the overall repertoire of cellular enzymes. They can
be beneficial yet accessory, like the diversity-generating elements, or even essential, like the telomerase reverse transcrip-
tases. Nowadays, ever-increasing numbers of domesticated RT-carrying genetic elements are being discovered. It may be
argued that domesticated RTs and reverse transcription in general is more widespread in cellular organisms than previously
thought, and that many important cellular functions, such as chromosome end maintenance, may evolve from an originally
selfish process of converting RNA into DNA.
DOI: 10.1134/S000629792311007X
Keywords: reverse transcription, RNA-dependent DNA polymerase, telomerase reverse transcriptase
Abbreviations: RT, reverse transcriptases.
* To whom correspondence should be addressed.
INTRODUCTION
At the dawn of molecular biology, when little was
known about the underlying molecular nature of bio-
logical phenomena, numerous theoretical papers were
attempting to foresee future discoveries and to make
viable predictions regarding molecular explanations of
fundamental genetic concepts. Notably, only a relatively
small fraction of such papers withstood the test of time
and the eventual experimental scrutiny that followed in
the years to come. Among such visionary papers, the
theoretical prediction by Alexey Olovnikov of terminal
DNA under-replication in linear chromosomes and of
the specialized enzyme that could overcome this prob-
lem [1,2] occupies a well-deserved place. While simulta-
neous recognition of the end-replication problem is also
credited to the paper by James Watson [3], its focus on
phage DNA avoided the requirement for a specialized
polymerase, shifting the emphasis on end-processing nu-
cleases instead.
The Nobel prize-winning discovery of telomerase,
the specialized polymerase which can add simple re-
petitive sequences to the ends of linear chromosomes
to compensate for terminal DNA loss after each round
of replication, has in turn followed a long and winding
path. In the initial report by Greider and Blackburn, the
discovered Tetrahymena enzyme was designated as a ter-
minal transferase [4], because the detected activity was
adding tandem repeats onto telomeric primers without
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BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
Fig. 1. The main types of reverse transcriptases (RT) from the three domains of life. a)Chronology of RT discovery. The main RT types described
in the text are colored as follows: viral RTs, shades of red; RTs of eukaryotic mobile elements, shades of green; prokaryotic RTs, shades of blue;
domesticated eukaryotic RTs, shades of purple. Domesticated RTs are underlined. The years correspond to the first reports of identification of ho-
mology to the RT catalytic core. The year 1971 marks the first report of the chromosome end under-replication problem [1]. b)Examples of struc-
tural organization of domesticated eukaryotic RTs. Bacterial retrons are included for comparison. The centrally positioned RT catalytic core is
represented by the seven conserved motifs separated by spacers of variable length, with distinctively long insertion loops 2a and 3a (also called IFD)
marked in red. The D..DD active site residues and their non-catalytic replacements are indicated. Additional domains on either side of the RT
core and thumb are as follows: TEN, telomerase essential N-terminal domain; TRBD, telomerase RNA binding domain; CTE, C-terminal exten-
sion; P, polyproline stretch; NLS, nuclear localization signal; Bromo, bromodomain; PROCN, PRO8 central domain; Endo, endonuclease-like;
Jab1/MPN, putative deubiquitinase-like domain. The scale is approximate. Domain composition is compiled from refs. [55, 57, 59].
an apparent template. An associated RNA template,
however, was subsequently identified as an integral com-
ponent of the ribonucleoprotein holoenzyme, providing
experimental evidence in support of RNA-dependent
DNA synthesis [5], although it was still considered pre-
mature to classify the telomerase enzyme as an authentic
reverse transcriptase.
The process of DNA synthesis that uses RNA as a
template is universally recognized under the term “re-
verse transcription”, and the corresponding enzyme that
can perform this reaction bears the name “reverse tran-
scriptase” (RT). Its experimental discovery by Temin and
Baltimore more than 50 years ago [6, 7], which was also
recognized by a Nobel prize, was similarly preceded by
Howard Temin’s conceptualization of DNA synthesis
on viral RNA template, known as “the provirus hypoth-
esis” [8]. Little did they know that in addition to discov-
ering the reverse flow of genetic information from viral
RNA to DNA, they also provided the foundation for the
discovery of self-replicating movable genetic elements
and for eventual realization that some of the accesso-
ry or even essential host functions can be taken over by
the descendants of such mobile elements. Remarkably,
RTs were discovered approximately at the time when the
chromosome end under-replication problem first came
to light (Fig.1).
EVOLUTION OF APPROACHES
TO RETROELEMENT DISCOVERY
Since their discovery in retroviruses, RT diversi-
ty underwent an amazing expansion from purely viral
constituents to a staggering variety of structural and
functional roles in eukaryotic and prokaryotic hosts
(Fig. 1a). After early advances in the field of virology,
which led to further discovery of reverse transcription in
the replicative cycles of hepadnaviruses and caulimovi-
ruses (collectively named pararetroviruses [9]) and were
facilitated by the availability of methods for virus isola-
tion and biochemical RT assays, the discovery potential
soon shifted towards detection of sequence homologies,
spurred by the advent of sequencing technologies and the
landmark identification of common amino acid sequence
motifs in the catalytic core of DNA polymerases from
reverse-transcribing viruses [10]. Since then, the search
for the aspartates forming the D..DD catalytic triad at
the RT active site has quickly become an integral part of
identification of novel RTs. In the RT discovery timeline
(Fig.1a), the underlying publications in which the char-
acteristic RT residues were first identified were given pri-
ority in comparison to those reporting initial biochemical
detection of RNA-dependent DNA polymerization. This
is because proper experimental validation of RT activity
ARKHIPOVA, YUSHENOVA175 6
BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
should inevitably include site-directed mutagenesis of the
active site residues, present in two of the seven conserved
motifs defining the RT catalytic core (Fig.1b).
The first half of the timeline, prior to 1990’s, is rep-
resented mainly by RTs from various types of viruses and
mobile genetic elements. Indeed, multicopy transposable
elements were one of the first components of eukaryotic
genomes to be cloned molecularly [11, 12], along with
other actively transcribed multicopy genes such as ribo-
somal DNA repeat units or histone gene clusters [13, 14].
The overall structural similarity between LTR-retro-
transposons and retroviruses immediately became appar-
ent upon their cloning from Drosophila and yeast [15].
However, the definitive proof of their close relationship
to retroviruses came from analysis of their complete nu-
cleotide sequences identifying the coding capacity for the
RT enzyme [16, 17]. Furthermore, characteristic blocks
of homology to the RT conserved motifs were soon iden-
tified not only in retrovirus-like transposable elements,
but also in fungal mitochondrial groupII mobile introns
and other types of multicopy eukaryotic transposons,
such as DIRS and LINE-like retrotransposons [18-21].
To conclude the first two decades of RT research, the
existence of RTs in bacteria was reported in the form
of retrons, multicopy extrachromosomal DNA–RNA
chimeric molecules connected through a 2′-5′ branch-
point [22,23].
The next temporal phase in RT discovery, while also
relying on detection of sequence homologies, was dom-
inated by RTs present in lower copy numbers, most of
which do not belong to transposable elements, but in-
stead represent single-copy host genes (Fig. 1a, under-
lined). In fact, the currently known eukaryotic retrotrans-
poson diversity has not expanded since the discovery of
Penelope-like retroelements (PLEs) [24]. The first and
most prominent case of RT domestication in eukary-
otes emerged with the proof that telomerase represents a
bonafide RT. Connecting the RT activity with the cor-
responding enzyme took a lot of time and effort, with
mis-identifications along the way [25], but the ultimate
success in identifying the telomerase catalytic subunit as
an RT came with identification of the conserved motifs
in the fingers and palm RT domains, validated by loss of
activity upon site-directed mutagenesis of the three in-
variant catalytic aspartates [26]. Thus, a single-copy RT
gene present in nearly all eukaryotic species was found to
be responsible for an essential host function of elongating
the ends of linear chromosomes to counteract terminal
DNA loss from under-replication, or marginotomy, as it
was originally named by Olovnikov [27]. Currently, new
RT types are mostly identified by computational mining,
taking advantage of the abundant genomic and metage-
nomic data. In the following sections, our aim is to briefly
characterize the RTs which belong to mobile genetic ele-
ments, and to compare to those which are domesticated
and accordingly non-mobile.
EUKARYOTIC MOBILE ELEMENTS:
RETROVIRUSES, PARARETROVIRUSES,
RETROTRANSPOSONS
To understand and compare the properties of viral
and mobile RTs, we need to consider the architectural
composition of conserved domains that occur in com-
bination with RT, as well as the adjacent gene content
within the mobilizable unit (Fig. 2). Interestingly, retro-
viruses, the discovery of which opened the era of RT re-
search, turned out to be strikingly similar to LTR-retro-
transposons, discovered over a decade later, in their gene
content, organization, and replication cycle, pointing at
their common evolutionary ancestry [16, 17, 28]. RTs of
hepadnaviruses can be broadly assigned to the base of the
viral/LTR branch of eukaryotic RTs, which harbors the
C-terminal RNase H domain to ensure replication in
the cytoplasm, avoiding the need to employ host nuclear
RNase Henzymes for destruction of RNA in the DNA–
RNA hybrid (Fig.2). Even more unusual is the case of
caulimoviruses, the RT of which is closely related to that
of Metaviridae (aka Ty3/mdg4(gypsy)-like LTR retro-
transposons), such that their ancestry is most likely of
hybrid nature, resulting from RT capture by a DNA virus
[29]. The Ty1/copia-like LTR retrotransposons (Pseudo-
viridae) conform to the general LTR structure, but show
a different domain order. All retrovirus-like elements
comprising the taxonomic order Ortervirales (Retroviri-
dae, Metaviridae, Pseudoviridae and Belpaoviridae) [29]
are mobilized with the aid of the integrase(IN), which
is responsible for insertion of a cDNA copy into new
chromosomal locations. A distinct group called DIRS
elements mobilizes by using tyrosine recombinase(YR)
instead of IN.
Non-LTR (or LINE-like) retrotransposons mobilize
without producing a cytoplasmic cDNA intermediate:
their RT uses the target-primed reverse transcription
(TPRT) mechanism to synthesize cDNA directly at the
chromosomal integration site nicked by one of the two
different types of associated endonuclease(EN), either
AP-like or REL-like. Finally, RTs of Penelope-like ele-
ments employ yet another EN type (GIY-YIG) for mo-
bilization, bringing the number of retrotransposon-as-
sociated endonuclease types to five. A more detailed
recent description of retromobility mechanisms can be
found in[30].
PROKARYOTIC MOBILE ELEMENTS:
GROUP II INTRONS, RETROPLASMIDS
Group II introns (G2I) are self-splicing retroele-
ments found in bacteria, some archaea, and eukaryotic
organelles [31]. First discovered in fungal mitochondria,
they were shown to possess the same structural organi-
zation in bacteria and archaea, and are widely regarded
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BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
Fig. 2. Domain architecture of the major RT types described in the text. For each type, a typical architecture is presented as revealed by the
CDART tool at NCBI [63]. Domain designation is according to the NCBI conserved domain database (CDD) [64]. The colors are assigned by
the CDART tool dynamically rather than following each domain specifically; to facilitate homology tracing, the RT and RNaseH (RH) domains
are connected with a dashed line. The circular arrangement follows the phylogenetic groupings in the center from ref.[55], with letters P, V, T,
and L corresponding to prokaryotic, virus-like, telomerase-like, and LINE-like retroelements; RVT genes form a separate group which has no
designation yet. Mobile elements contain six different types of associated nucleases/phosphotransferases mentioned in the text: IN, AP, REL, YR,
GIY-YIG, HNH. Virus-like elements are named according to ICTV classification [29]. Domesticated eukaryotic RTs (TERT, RVT) are designated
as Genes.
as evolutionary precursors to eukaryotic spliceosomal
introns. Their retromobility is ensured by the combined
action of the catalytically active RNA, which functions
as a ribozyme in the self-splicing and reverse-splicing
reactions, and the intron-encoded RT, which synthesiz-
es a cDNA copy of the intron RNA at the target site,
using the TPRT mechanism.
Retroplasmids were found in fungal mitochon-
dria [32] and for a long time served as a model system
to study the unconventional priming modes by reverse
transcriptases (protein priming, when RT uses the hy-
droxyl group of tyrosine or serine residues for priming,
or denovo RT initiation, which does not use any primer
at all). Their distribution is still quite limited, as there
are only a few dozen fungal species harboring them, out
of hundreds of sequenced fungal genomes. As extrachro-
mosomal entities, they are not expected to undergo in-
tegration, but technically form part of the mobilome due
to their ability to replicate autonomously.
NON-MOBILE RETROELEMENTS
IN BACTERIA AND ARCHAEA:
RETRONS, DGRs, Abi/UG,
Cas-ASSOCIATED, G2I-LIKE
Retrons are peculiar domesticated bacterial elements
composed of covalently linked RNA and multicopy sin-
gle-stranded DNA (msDNA) in a single branched mole-
cule connected by a 2′-5′ phosphodiester linkage [22, 23].
Each retron module encodes an RT protein sequence,
a non-coding RNA which is reverse-transcribed by the
RT to form the chimeric single-stranded DNA/RNA
molecules, and an effector gene needed for anti-phage
activity. Despite being the first prokaryotic non-mobile
retroelements discovered over 30 years ago, the cellular
function of retrons was elucidated only in 2020 [33-35].
Retrons confer host defense against a broad range of
phages via abortive infection and subsequent cell death.
They are widespread in bacteria, being one of the main
ARKHIPOVA, YUSHENOVA1758
BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
components of bacterial immune systems. However, the
exact mechanisms by which they confer phage resistance
via reverse transcription are still unknown. The co-oc-
currence of RT in tripartite modules with template RNA
and a variety of putative effector genes suggests their
direct interaction in eliciting anti-phage response [36].
Indeed, such interaction was observed in a complex be-
tween RT, its cognate msDNA, and the linked effector
nucleoside deoxyribosyltransferase [37].
Diversity-generating retroelements (DGRs) are non-
mobile RTs that diversify adjacent target DNA sequenc-
es in bacteria, archaea, and viruses [38,39]. Despite be-
ing non-essential retroelements, DGRs are nevertheless
beneficial for their hosts. In the best-described model
system, DGRs generate diversity in the C-terminal vari-
able region of target protein gene(mtd) of the Bordetella
pertussis bacteriophage BPP-1. The resulting hypervari-
ability in the phage tail protein, the region that contacts
the bacterial cell during infection, allows the phage
to infect bacterial cells with altered surface receptors.
By utilizing error-prone reverse transcription, DGRs
help to increase diversity in gene products, especially
those involved in ligand-binding and host attachment.
It is still a mystery how the adenine specificity of tar-
geted hypermutagenesis is accomplished. Moreover,
inspection of adjacent genes in DGR modules suggests
that hypervariability targets may not be limited to tro-
pism switching and surface display [40,41].
Abortive infection systems (Abi), represented by
AbiA, AbiK, and Abi-P2, are bacterial retroelements that
serve to protect certain bacteria from phage infections.
These genes are only found in some Bacilli (mostly in
Lactococcus lactis) genomes as plasmid-encoded genes
(AbiA and AbiK), and on P2-like prophages in Esche-
richia coli (Abi-P2). While their detailed mechanism of
action is still unknown, Abi proteins are required for
blocking phage replication followed by programmed cell
death or phage exclusion [42, 43]. Interestingly, the AbiK
protein was shown to perform non-templated DNA po-
lymerization invitro and is covalently attached to DNA,
which is indicative of protein priming [44]. Thus, Abi
represent another, besides retrons, type of active RT
which confers advantage to a subset of bacteria when
attacked by phages. Of note, AbiP2 and AbiK RTs are
exceptional in forming compact trimers or hexamers in
solution, as well as in lacking the RT thumb domain,
which is replaced by the all-helical domain composed of
HEAT repeats [45, 46]. A substantial proportion of the
so-called unknown groups (UG) [47], some of which
were independently called DRT (defense RT) [33], were
reported in earlier surveys as unassignable to a specific
RT type, but were later found to be related to Abi RTs
and to play a role in antiphage defense, with enrichment
in the so-called defense islands, which contain a variety
of other genes providing protection against invading for-
eign DNA [33,45].
RT-Cas: RT domains were found near CRISPR-as-
sociated genes or even fused to Cas proteins [48-50].
Potentially, these RTs can confer bacterial immunity
by performing cDNA synthesis on RNA from bacte-
riophages, and were indeed shown to mediate heritable
acquisition of short sequence segments (spacers) from
foreign RNA elements [51]. Fusion to Cas proteins is
not necessary, although it allows more efficient cooper-
ation of the interacting domains [52]. These RTs are not
monophyletic, having been co-opted into CRISPR-Cas
systems from several bacterial RT lineages [50].
Group II intron-like RTs (G2L), a heterogeneous
group of non-mobile RTs that share sequence similari-
ty with G2I but lack the ribozyme moiety, was first de-
scribed in [48]. Recently, it was found that G2L RT from
Pseudomonas aeruginosa (G2L4 RT) is involved in trans-
lesion DNA synthesis and double-strand break repair
via microhomology-mediated end-joining (MMEJ) [53].
Interestingly, the substitution of YADD to YIDD in the
G2L4 RT active site is responsible for a shift towards
performing MMEJ instead of primer extension, which is
characteristic for canonical G2I RTs with YADD at the
catalytic site. Nevertheless, a canonical G2I RT was also
capable of performing DNA repair.
NON-MOBILE EUKARYOTIC RTs
AND THEIR DERIVATIVES:
TELOMERASE, RVT, PRP8
Telomerase reverse transcriptase (TERT), as de-
scribed above (Fig. 1b), is undoubtedly the most well-
known RT with a crucial cellular function. Based on the
main function of maintaining the length of linear chro-
mosomes, it has well-described roles in aging, cancer,
and other human diseases (aplastic anemia, Cri du chat
syndrome, Dyskeratosis congenita, etc.). Multiple ap-
proaches are being developed to target active telomerase
and the associated TERT RNA template pharmaceuti-
cally in the context of anti-cancer therapy and age-relat-
ed diseases (recently compiled in[54]).
Reverse transcriptase-related genes (rvt) (Fig. 1b)
are the most recently discovered type of domesticated
eukaryotic RTs widespread in fungi and sporadically oc-
curring in selected plants, protists, and invertebrates [55].
Strikingly, these genes are present in both prokary-
otes and eukaryotes, in contrast to all other RT types.
Notably, RVTs from all bacterial phyla form a mono-
phyletic group, suggesting that they were not horizon-
tally transferred from eukaryotes as initially thought,
but may have been present in Bacteria prior to eukaryo-
genesis [56]. Rvt genes encode active RT-like proteins
that in fungi can polymerize both dNTPs and NTPs.
RVT proteins are also capable of protein priming. While
biological function of rvt genes is not yet fully under-
stood, they are clearly preserved by natural selection,
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BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
indicating their importance for host cells. These genes
are strongly activated by starvation and certain antibi-
otics in fungi, suggesting their involvement in response
to these agents[55].
Pre-mRNA-processing factor 8 (Prp8) is an unusu-
al domesticated RT derivative that lost two out of three
catalytic aspartates, thereby losing the ability to po-
lymerize nucleotides [57]. Yet, Prp8 is an essential part
of eukaryotic spliceosome regulating its assembly and
conformation during pre-mRNA splicing [58]. The RT
moiety of Prp8 was proposed to originate from mobile
group II introns [59], giving us one more example of
how during evolution selfish retrotransposons can give
rise to essential components of eukaryotic cells, in this
case as a structural element which comprises the cen-
tral U5-snRNA-binding part of a large multi-domain
protein (Fig. 1b). The lack of catalytic residues and very
high sequence conservation due to evolutionary con-
straints imposed by spliceosome function impedes un-
ambiguous phylogenetic placement of this RT-derived
domain, but its origin undoubtedly dates back to the last
common ancestor of all eukaryotes.
CONCLUDING REMARKS
From the RT descriptions summarized above, it is
easy to note that the RT types discovered in earlier years
generally originated from abundant, high-copy-num-
ber sources – initially from viruses, and subsequently
from cellular multicopy mobile genetic elements: from
LTR, DIRS, and non-LTR retrotransposons in eukary-
otes, to prokaryotic mobile group II introns and retro-
plasmids, and to retrons producing abundant branched
DNA–RNA molecules in bacterial cells. Retromobility
is typically conferred by a specific type of endonucle-
ase associated with each mobile element, providing the
means for intrachromosomal insertion of a cDNA copy.
At the initial stages, many eukaryotic TEs were identi-
fied by their ability to cause insertional mutations with
visible phenotypes in strains experiencing transposition
of multicopy elements [60]. It is now clear that RTs can
perform a large variety of functions besides their role
in proliferation of selfish genetic elements. We argue
that the diversity of domesticated RTs has been gross-
ly underestimated and their role has been substantially
undervalued, with plenty of opportunities existing for
RT recruitment by the host cells despite their overall
non-essential nature and patchy distribution. It is not
surprising that sometimes it may take a long time, even
decades, from initial identification of an element to the
proper assignment of a host function, if the selective ad-
vantage to the host is conditional. The telomerase RT,
a single-copy gene, represents a notable exception in
being ubiquitously present throughout eukaryotes, and
the revelation that it encodes a specialized RT, i.e.,
an enzyme previously thought to be characteristic only
of viruses and mobile elements, has truly revolutionized
the field [26]. Still, even the critical function of telomere
maintenance can be supported by independent backup
pathways [61].
It is worth emphasizing that RT domestication in
eukaryotes is invariably associated with the appearance
of additional functional domains that would prevent it
from spurious cDNA synthesis using random primer/
template combinations. Generally, synthesis of cDNA
copies on random host RNA templates is not expected to
benefit the host cell and should be prevented. Themost
straightforward way is to eliminate catalytic activity by
replacing active site residues, as in Prp8. Another op-
tion is to change the configuration of the active site by
inserting additional structural loops, as in RVT genes.
Finally, TERTs have achieved strict substrate specificity
via a high degree of specialization towards an unlinked
highly structured RNA (called TER or TR), which con-
tains a short reverse-complement of the telomeric repeat
unit serving as a template, and interacts specifically with
the TRBD domain to perform highly processive DNA
synthesis by target-primed reverse transcription (TPRT)
off the 3′-ends of exposed short G-rich tandem repeats
at the ends of linear chromosomes [62]. It is fascinating
to realize that the specialized enzyme predicted to over-
come terminal DNA loss and to preserve chromosome
integrity takes its origins from mobile elements initially
poised to disrupt chromosomal stability.
Contributions. I.A. and I.Y. contributed to con-
ceptualization, writing, and editing of the article; the
figures were adapted by I.A. from her presentation at
the 2022 Cold Spring Harbor meeting “Fifty Years of
Reverse Transcriptase”.
Acknowledgments. This contribution honors the
memory of Alexey Olovnikov, in lieu of a planned
in-person discussion, which was originally expected to
take place in Moscow but never did.
Funding. The work in the laboratory is funded by
grants from the U.S. National Institutes of Health to I.A.
(R01GM111917) and the U.S. National Science Founda-
tion to I.A. and I.Y. (MCB-2139001, MCB-2326038).
Ethics declarations. Authors declare no conflict of
interest. This article contains no description of studies
involving human subjects or animals performed by any
of the authors.
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