View source for Biology:Post-transcriptional modification

{{Short description|RNA processing within a biological cell}}
{{missing information||sections for RNA other than mRNA|date=October 2020}}
{{genetics sidebar}}
'''Transcriptional modification''' or '''co-transcriptional modification''' is a set of biological processes common to most [[Biology:Eukaryote|eukaryotic]] cells by which an [[Biology:RNA|RNA]] [[Biology:Primary transcript|primary transcript]] is chemically altered following [[Biology:Transcription|transcription]] from a [[Biology:Gene|gene]] to produce a mature, functional RNA molecule that can then leave the [[Biology:Cell nucleus|nucleus]] and perform any of a variety of different functions in the cell.<ref>{{cite journal | vauthors = Kiss T | title = Small nucleolar RNA-guided post-transcriptional modification of cellular RNAs | journal = The EMBO Journal | volume = 20 | issue = 14 | pages = 3617–22 | date = July 2001 | pmid = 11447102 | pmc = 125535 | doi = 10.1093/emboj/20.14.3617 }}</ref> There are many types of post-transcriptional modifications achieved through a diverse class of molecular mechanisms.

One example is the conversion of precursor [[Biology:Messenger RNA|messenger RNA]] transcripts into mature messenger RNA that is subsequently capable of being [[Biology:Translation|translated]] into [[Biology:Protein|protein]]. This process includes three major steps that significantly modify the chemical structure of the RNA molecule: the addition of a 5' cap, the addition of a 3' [[Biology:Polyadenylation|polyadenylated]] tail, and [[Biology:RNA splicing|RNA splicing]]. Such processing is vital for the correct translation of eukaryotic [[Biology:Genome|genome]]s because the initial precursor mRNA produced by transcription often contains both [[Biology:Exon|exon]]s (coding sequences) and [[Biology:Intron|intron]]s (non-coding sequences); splicing removes the introns and links the exons directly, while the cap and tail facilitate the transport of the mRNA to a [[Biology:Ribosome|ribosome]] and protect it from molecular degradation.<ref name="Stryer836">{{Harvnb|Berg|Tymoczko|Stryer|2007|Ref=CITEREFBergTymoczkoStryer2008|p=836}}</ref>

Post-transcriptional modifications may also occur during the processing of other transcripts which ultimately become [[Biology:Transfer RNA|transfer RNA]], [[Biology:Ribosomal RNA|ribosomal RNA]], or any of the other types of RNA used by the cell.

== {{anchor|mRNA_processing}}mRNA processing ==

<!-- NOTE: The gene structure image templates below are in a small div box they scroll properly on mobile and tablet screens (as of 2015) -->
{| style="clear:right; float: right;"
|-
|{{Eukaryote_gene_structure}}
{{Prokaryote_gene_structure}}
|}


=== 5' processing ===

==== Capping ====

Capping of the pre-mRNA involves the addition of 7-methylguanosine (m<sup>7</sup>G) to the 5' end. To achieve this, the terminal 5' phosphate requires removal, which is done with the aid of enzyme [[Biology:RNA triphosphatase|RNA triphosphatase]]. The enzyme guanosyl transferase then catalyses the reaction, which produces the diphosphate 5' end. The diphosphate 5' end then attacks the alpha phosphorus atom of a [[Chemistry:Guanosine triphosphate|GTP]] molecule in order to add the [[Chemistry:Guanine|guanine]]  residue in a 5'5' triphosphate link. The enzyme [[Biology:MRNA (guanine-N7-)-methyltransferase|(guanine-''N''<sup>7</sup>-)-methyltransferase]] ("cap MTase") transfers a methyl group from S-adenosyl methionine to the guanine ring.<ref>{{cite journal | vauthors = Yamada-Okabe T, Mio T, Kashima Y, Matsui M, Arisawa M, Yamada-Okabe H | title = The Candida albicans gene for mRNA 5-cap methyltransferase: identification of additional residues essential for catalysis | journal = Microbiology | volume = 145 ( Pt 11) | issue = 11 | pages = 3023–33 | date = November 1999 | pmid = 10589710 | doi = 10.1099/00221287-145-11-3023 | doi-access = free }}</ref> This type of cap, with just the (m<sup>7</sup>G) in position is called a cap 0 structure. The [[Chemistry:Ribose|ribose]] of the adjacent [[Biology:Nucleotide|nucleotide]] may also be methylated to give a cap 1. Methylation of nucleotides downstream of the RNA molecule produce cap 2, cap 3 structures and so on. In these cases the methyl groups are added to the 2' OH groups of the ribose sugar.
The cap protects the 5' end of the primary RNA transcript from attack  by [[Biology:Ribonuclease|ribonuclease]]s that have specificity to the 3'5' [[Biology:Phosphodiester bond|phosphodiester bond]]s.<ref name="CITEREFBiochemistry1">{{Harvnb|Hames|Hooper|2006|Ref=CITEREFHamesHopper2008|p=221}}</ref>

=== 3' processing ===

==== Cleavage and polyadenylation ====
{{main|Biology:Polyadenylation}}

The pre-mRNA processing at the 3' end of the RNA molecule involves cleavage of its 3' end and then the addition of about 250 [[Chemistry:Adenine|adenine]] residues to form a poly(A) tail. The cleavage and adenylation reactions occur primarily if a [[Biology:Polyadenylation|polyadenylation signal sequence]] (5'- AAUAAA-3') is located near the 3' end of the pre-mRNA molecule, which is followed by another sequence, which is usually '''(5'-CA-3')''' and is the site of cleavage. A '''GU-rich sequence''' is also usually present further downstream on the pre-mRNA molecule. More recently, it has been demonstrated that alternate signal sequences such as UGUA upstream off the cleavage site can also direct cleavage and polyadenylation in the absence of the AAUAAA signal. 
It is important to understand that these two signals are not mutually independent and often coexist. After the synthesis of the sequence elements, several multi-subunit [[Biology:Proteins|proteins]] are transferred to the RNA molecule. The transfer of these sequence specific binding proteins [[Biology:Cleavage and polyadenylation specificity factor|cleavage and polyadenylation specificity factor]] (CPSF), Cleavage Factor I (CF I) and [[Biology:Cleavage stimulation factor|cleavage stimulation factor]] (CStF) occurs from RNA Polymerase II. The three factors bind to the sequence elements. The AAUAAA signal is directly bound by CPSF. For UGUA dependent processing sites, binding of the multi protein complex is done by Cleavage Factor I (CF I). The resultant protein complex formed contains additional cleavage factors and the enzyme Polyadenylate Polymerase (PAP). This complex cleaves the RNA between the polyadenylation sequence and the GU-rich sequence at the cleavage site marked by the (5'-CA-3') sequences. Poly(A) polymerase then adds about 200 adenine units to the new 3' end of the RNA molecule using [[Chemistry:Adenosine triphosphate|ATP]] as a precursor. As the poly(A) tail is synthesized, it binds multiple copies of poly(A)-binding protein, which protects the 3'end from ribonuclease digestion by enzymes including the [[Biology:CCR4-Not|CCR4-Not]] complex.<ref name="CITEREFBiochemistry1"/>

=== Introns Splicing ===
{{main|Biology:RNA splicing}}

RNA splicing is the process by which [[Biology:Intron|intron]]s, regions of RNA that do not code for proteins, are removed from the pre-mRNA and the remaining [[Biology:Exon|exon]]s connected to re-form a single continuous molecule. Exons are sections of mRNA which become "expressed" or translated into a protein. They are the coding portions of a mRNA molecule.<ref>{{Cite book|title=Biology|publisher=Mgraw hill education|year=2014|isbn=978-981-4581-85-1|pages=241–242}}</ref> Although most RNA splicing occurs after the complete synthesis and end-capping of the pre-mRNA, transcripts with many exons can be spliced co-transcriptionally.<ref name="Lodish_2007">{{cite book |vauthors=Lodish HF, Berk A, Kaiser C, Krieger M, Scott MP, Bretscher A, Ploegh H, Matsudaira PT | title = Molecular Cell .Biology | publisher = WH Freeman | location = San Francisco | year = 2007 | isbn = 978-0-7167-7601-7 | chapter = Chapter 8: Post-transcriptional Gene Control }}</ref> The splicing reaction is catalyzed by a large protein complex called the [[Biology:Spliceosome|spliceosome]] assembled from proteins and [[Biology:Small nuclear RNA|small nuclear RNA]] molecules that recognize splice sites in the pre-mRNA sequence. Many pre-mRNAs, including those encoding [[Biology:Antibody|antibodies]], can be spliced in multiple ways to produce different mature mRNAs that encode different protein sequences. This process is known as [[Biology:Alternative splicing|alternative splicing]], and allows production of a large variety of proteins from a limited amount of DNA.

=== Histone mRNA processing ===
{{Main|Biology:Histone}}

Histones H2A, H2B, H3 and H4 form the core of a [[Biology:Nucleosome|nucleosome]] and thus are called core histones. Processing of core histones is done differently because typical histone mRNA lacks several features of other eukaryotic mRNAs, such as poly(A) tail and introns. Thus, such mRNAs do not undergo splicing and their 3' processing is done independent of most cleavage and polyadenylation factors. Core histone mRNAs have a special stem-loop structure at 3-prime end that is recognized by a stem–loop binding protein and a downstream sequence, called histone downstream element (HDE) that recruits [[Biology:U7 small nuclear RNA|U7 snRNA]]. Cleavage and polyadenylation specificity factor 73 cuts mRNA between stem-loop and HDE<ref name="His mRNA">{{cite journal | vauthors = Marzluff WF, Wagner EJ, Duronio RJ | title = Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail | journal = Nature Reviews. Genetics | volume = 9 | issue = 11 | pages = 843–54 | date = November 2008 | pmid = 18927579 | pmc = 2715827 | doi = 10.1038/nrg2438 }}</ref>

Histone variants, such as H2A.Z or H3.3, however, have introns and are processed as normal mRNAs including splicing and polyadenylation.<ref name="His mRNA" />

== See also ==

*[[Biology:Post-translational modification|Post-translational modification]]
*[[Biology:RNA editing|RNA editing]]
*[[Biology:RNA-Seq|RNA-Seq]]

== References ==
{{reflist|32em}}

== Further reading ==
{{refbegin|32em}}
* {{cite book | last1=Berg | first1=Jeremy M. | last2=Tymoczko | first2=John L. | name-list-style=vanc | last3=Stryer | first3=Lubert |  title=Biochemistry | year=2007 | place={{wipe|New York City}} | edition=6 | publisher=WH Freeman & Co. | isbn=978-0-7167-6766-4 | url-access=registration | url=https://archive.org/details/biochemistry0006berg }}
* {{cite book
  | last1=Hames | first1=David | last2=Hooper | first2=Nigel | name-list-style = vanc
  | title=Instant Notes Biochemistry
  | journal=Annales de Biologie Clinique | year=2006 | volume=58 | issue=6 | pages=767 | place=Leeds | edition=3 | publisher=Taylor and Francis
  | pmid=11098183 | isbn=978-0-415-36778-3
  }}
* {{cite journal | vauthors = Sun WJ, Li JH, Liu S, Wu J, Zhou H, Qu LH, Yang JH | title = RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data | journal = Nucleic Acids Research | volume = 44 | issue = D1 | pages = D259-65 | date = January 2016 | pmid = 26464443 | pmc = 4702777 | doi = 10.1093/nar/gkv1036 }}
* {{cite journal | vauthors = Machnicka MA, Milanowska K, Osman Oglou O, Purta E, Kurkowska M, Olchowik A, Januszewski W, Kalinowski S, Dunin-Horkawicz S, Rother KM, Helm M, Bujnicki JM, Grosjean H | title = MODOMICS: a database of RNA modification pathways--2013 update | journal = Nucleic Acids Research | volume = 41 | issue = Database issue | pages = D262-7 | date = January 2013 | pmid = 23118484 | pmc = 3531130 | doi = 10.1093/nar/gks1007 }}
* {{cite journal | vauthors = Cantara WA, Crain PF, Rozenski J, McCloskey JA, Harris KA, Zhang X, Vendeix FA, Fabris D, Agris PF | title = The RNA Modification Database, RNAMDB: 2011 update | journal = Nucleic Acids Research | volume = 39 | issue = Database issue | pages = D195-201 | date = January 2011 | pmid = 21071406 | pmc = 3013656 | doi = 10.1093/nar/gkq1028 }}
{{refend}}

*{{MeshName|Post-Transcriptional+RNA+Modification}}

{{Post transcriptional modification}}
{{MolBioGeneExp}}

[[Category:Cell biology]]
[[Category:Molecular biology]]
[[Category:Gene expression]]
[[Category:RNA]]

{{Sourceattribution|Post-transcriptional modification}}