Modified Nucleic Acids in Biology and Medicine

456 Pages·2016·10.16 MB·English

by  Stefan Jurga

RNA Technologies
Stefan Jurga
Volker A. Erdmann
Jan Barciszewski E ditors
Modifi ed
Nucleic Acids
in Biology
and Medicine
RNA Technologies
Moreinformationaboutthisseriesathttp://www.springer.com/series/8619
Stefan Jurga (cid:129) Volker A. Erdmann (cid:129)
Jan Barciszewski
Editors
Modified Nucleic Acids
in Biology and Medicine
Editors
StefanJurga VolkerA.Erdmann(Deceased)
NanobiomedicalCenter FormerlyatInstituteofChemistryand
AdamMickiewiczUniversity Biochemistry
Poznan´ FreeUniversityBerlin
Poland Berlin
Germany
JanBarciszewski
InstituteoftheBioorganic
ChemistryofthePolishAcademy
ofSciences
Poznan´
Poland
ISSN2197-9731 ISSN2197-9758 (electronic)
RNATechnologies
ISBN978-3-319-34173-6 ISBN978-3-319-34175-0 (eBook)
DOI10.1007/978-3-319-34175-0
LibraryofCongressControlNumber:2016944798
©SpringerInternationalPublishingSwitzerland2016
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission
or information storage and retrieval, electronic adaptation, computer software, or by similar or
dissimilarmethodologynowknownorhereafterdeveloped.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexempt
fromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse.
Thepublisher,theauthorsandtheeditorsaresafetoassumethattheadviceandinformationinthis
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authors or the editors give a warranty, express or implied, with respect to the material contained
hereinorforanyerrorsoromissionsthatmayhavebeenmade.
Printedonacid-freepaper
ThisSpringerimprintispublishedbySpringerNature
TheregisteredcompanyisSpringerInternationalPublishingAGSwitzerland
Preface
The Power of Modified Nucleic Acids
WiththisvolumeoftheseriesRNAtechnologies,weaimtocovervariousaspects
ofnucleicacidmodifications.Thisisaninterestingissueinthestudyofmacromo-
lecularcomponentsofcells.
DNA and RNA are key molecules of the cell. The structure, function, and
reactivity of DNA and RNA are central to molecular biology and are crucial for
the understanding of complex biological processes. For a long time DNA was
considered as the most important molecule of all biology and the key of life.
However DNA is not the be all and end all of the living cell, but it appears as an
important by-product of the RNA evolution. Deoxyribonucleotides as DNA pre-
cursors are synthesized by specific enzymatic modification of ribonucleotides in
which the20-hydroxyl groupoftheribosemoietyisreplacedby20-hydrogenwith
ribonucleotide reductase. One of these DNA bases, thymine, is produced by
methylation of uracil. There are a significant number of adenosines and cytidines
ingenomicDNAconvertedbyspontaneousorenzymaticdeaminationtohypoxan-
thine and uracil, respectively. Cytosine can be methylated to 5-methylcytosine
derivative with not only a coding capacity but also a regulatory potential. These
datasuggestthatDNAlookssimilartoamodifiedRNAmoleculealthoughchem-
ically more stable than RNA. In the eukaryotic cell, all postreplicative modifica-
tionsofDNAshowedafewpercentofallbases.CellularDNAsandRNAscanbe
chemicallymodifiedinmorethan100differentways.Someofthesemodifications
tonucleicacidsarerandomorspontaneousandtheirformationrequiressignificant
energyfromthecell.Thebroadrangeofchemicalmodificationstonucleicacidsis
notrestrictedtosimplenucleophilicsubstitutionbutextendstooxidativereactions
andC–H activationby various agents.The modificationsmight occur onDNA as
well as different types of RNA such as transfer ribonucleic acids (tRNAs), ribo-
somal RNA (rRNA), messenger RNA (mRNA), and other noncodings (ncRNAs).
Among them, tRNAs represent ca 15% of the total cellular RNAs and are highly
v
vi Preface
stable.TheprimaryroleoftRNAistodeliveraminoacidstothepolypeptidechain
during protein translation. tRNA molecules 73–93 nucleotides long are heavily
modified types ofribonucleic acid. tRNA modifications (upto 25%) are dynamic
and adaptive to different environmental changes. Modified nucleosides of tRNAs
playanimportantroleinthetranslationofthegeneticcode.
The modified nucleosides are utilized to fine tune nucleic acids structure and
function. These modifications are dynamic and participate in regulating diverse
biologicalpathways.Theycanalsobeusedasspecificmarkersofdifferentstatesof
cellsanddiseasesorpathologies.Theprocess ofRNAsturnoverisdirectlycorre-
lated to their presence in the human. Evaluation of modified nucleosides might
become novel markers to facilitate early clinical diagnosis of cancer to improve
humancancerriskassessment.
Nucleoside methylation and other nucleic acid modifications are of a great
interest, prompted by the discovery of methylation and active demethylation of
DNA and RNA. In eukaryotic genomic DNA, 5-methylcytosine is a well-know
epigeneticmodificationandisalsoknowntoexistinbothrRNAandtRNA.
In response to oxidative stress caused by reactive oxidative species (ROS) as
wellasnutrientdepletionandothergrowtharrestconditions,modifiednucleotides
are synthesized in the cell to serve various purposes. Accidental non-enzymatic
methylation or oxidation of a base in a DNA and RNA, in addition to the normal
enzymatic methylation processes, induces serious problems for living cells, espe-
cially for DNA, for which abnormal alkylation can be mutagenic. To remove this
type of modification, the cell has developed oxidative mechanisms in an
indirectway.
The recent development of high-throughput sequencing technologies has
enabled us to identify tRNA-derived RNA fragments. It seems that they are not
by-products from random degradation but rather functional molecules that can
regulatetranslationandgeneexpression.
IttakesalargeeffecttomapRNAmodificationsgloballyaswellastoidentify
the cellular function as writers, readers, and erasers for each modification. Basic
cellularpathwaysuseubiquitousmetabolitesandcoenzymestotransfermethyland
aminoacidgroups,isoprenoids,sugars,phosphates,andvariousmetabolitenucleic
acidconjugateshavebeenfoundthataffectafunctionalityoftheirspecifictargets.
Theturnoverofnucleicacidsincreaseswhencellproliferationtakesplace.Any
disease or metabolic alteration affecting RNA turnover consequently results in
alterednucleosideexcretionpatterns,leadingtothehypothesisthatRNAmetabo-
lites may be used as early indicators of disease. In addition, increased RNA
metabolism with altered nucleoside excretion patterns related to metabolic disor-
ders such as cancer may be suitable markers to facilitate the monitoring of thera-
peuticintervention.
Inthisbookwehavecollectedworkdescribingmodifiednucleosides,naturally
occurring or chemically synthesized nucleic acids. Their role in cell biology has
huge potential for application in medicine. Further research frontiers and new
developmentsarealsodiscussed.
Preface vii
In total there are 18 chapters. Five of them deal with tRNAs and their modifi-
cations inrelationtobiomedical applications. Three discussmodifiednucleosides
includingN6-methyladenosineand8-hydroxyguanosineaswellas20-O-methylated
ribonucleotides. A very interesting chapter describes the role of diadenosine
tetraphosphate in health and disease. Similar properties are described for circular
RNAs and for modified therapeutic oligonucleotides. Other chapters describe the
propertiesofmodifiedoligonucleotides.
Poznan´ StefanJurga
Berlin VolkerA.Erdmann
Poznan´ JanBarciszewski
January2016
ThiSisaFMBlankPage
RNA Around the Clock: Volker A. Erdmann
in Memoriam
On September 11, 2015 we lost our colleague and dear friend Professor Volker
A.ErdmannfromtheInstituteofChemistry–Biochemistry,Freie Universita¨tBer-
lin,Germany.HewasbornonFebruary8,1941inStettin(Germany,nowPoland)
and later became a U.S. citizen. In 1963 he earned his B.A. in Chemistry and in
1966anM.Sc.inBiochemistryfromtheUniversityofNewHampshire,Durham,N.
H., USA (advisor: Prof. Dr. E.J. Herbst). From 1966 to 1969 at the Max-Planck-
Institut f€ur experimentelle Medizin, G€ottingen, Germany, and Technische
Universita¨tBraunschweig,Germany,heobtainedaDr.rer.nat.degreeinBiochem-
istry with minors in Chemistry and Microbiology (advisor: Prof. Dr. F. Cramer).
After an NIH postdoctoral fellowship with Prof. Dr. M. Nomura at University of
Wisconsin,Madison,Wisc.,USA,in1971hebecamearesearchgroupleaderatthe
Max-Planck-Institut f€ur Molekulare Genetik in Berlin at the Department led by
Prof. Dr. H.G. Wittmann. In 1978 Volker did Habilitation in Biochemistry and
MolecularBiologyattheFreieUniversita¨tatBerlin,Germany.
ix