Editing Lambda phage (section)

===Lysogenic (or lysenogenic) life cycle===
{{Main|Lysogenic cycle}}
The lysogenic lifecycle begins once the cI protein reaches a high enough concentration to activate its promoters, after a small number of infections.
# The 'late early' transcripts continue being written, including ''xis'', ''int'', ''Q'' and genes for replication of the lambda genome.
# The stabilized cII acts to promote transcription from the ''P<sub>RE</sub>'', ''P<sub>I</sub>'' and ''P<sub>antiq</sub>'' promoters.
# The ''P<sub>antiq</sub>'' promoter produces antisense mRNA to the ''Q'' gene message of the ''P<sub>R</sub>'' promoter transcript, thereby switching off Q production. The ''P<sub>RE</sub>'' promoter produces antisense mRNA to the cro section of the ''P<sub>R</sub>'' promoter transcript, turning down cro production, and has a transcript of the ''cI'' gene. This is expressed, turning on cI repressor production. The ''P<sub>I</sub>'' promoter expresses the ''int'' gene, resulting in high concentrations of Int protein. This int protein integrates the phage DNA into the host chromosome (see "Prophage Integration").
# No Q results in no extension of the ''P<sub>R'</sub>'' promoter's reading frame, so no lytic or structural proteins are made. Elevated levels of int (much higher than that of xis) result in the insertion of the lambda genome into the hosts genome (see diagram). Production of cI leads to the binding of cI to the ''OR1'' and ''OR2'' sites in the ''P<sub>R</sub>'' promoter, turning off  ''cro'' and other early gene expression. cI also binds to the ''P<sub>L</sub>'' promoter, turning off transcription there too.
# Lack of cro leaves the ''OR3'' site unbound, so transcription from the ''P<sub>RM</sub>'' promoter may occur, maintaining levels of cI.
# Lack of transcription from the ''P<sub>L</sub>'' and ''P<sub>R</sub>'' promoters leads to no further production of cII and cIII.
# As cII and cIII concentrations decrease, transcription from the ''P<sub>antiq</sub>'', ''P<sub>RE</sub>'' and ''P<sub>I</sub>'' stop being promoted since they are no longer needed.
# Only the ''P<sub>RM</sub>'' and ''P<sub>R'</sub>'' promoters are left active, the former producing cI protein and the latter a short inactive transcript. The genome remains inserted into the host genome in a dormant state.

The prophage is duplicated with every subsequent cell division of the host. The phage genes expressed in this dormant state code for proteins that repress expression of other phage genes (such as the structural and lysis genes) in order to prevent entry into the lytic cycle. These repressive proteins are broken down when the host cell is under stress, resulting in the expression of the repressed phage genes. Stress can be from [[starvation]], [[poison]]s (like [[antibiotics]]), or other factors that can damage or destroy the host. In response to stress, the activated prophage is excised from the DNA of the host cell by one of the newly expressed gene products and enters its lytic pathway.

====Prophage integration====
The integration of phage λ takes place at a special attachment site in the bacterial and phage genomes, called ''att<sup>λ</sup>''. The sequence of the bacterial att site is called ''attB'', between the ''gal'' and ''bio'' operons, and consists of the parts B-O-B', whereas the complementary sequence in the circular phage genome is called ''attP'' and consists of the parts P-O-P'. The integration itself is a sequential exchange (see [[genetic recombination]]) via a [[Holliday junction]] and requires both the phage protein Int and the bacterial protein IHF (''integration host factor''). Both Int and IHF bind to ''attP'' and form an intasome, a DNA-protein-complex designed for [[site-specific recombination]] of the phage and host DNA. The original B-O-B' sequence is changed by the integration to B-O-P'-phage DNA-P-O-B'. The phage DNA is now part of the host's genome.<ref>{{cite journal | vauthors = Groth AC, Calos MP | title = Phage integrases: biology and applications | journal = Journal of Molecular Biology | volume = 335 | issue = 3 | pages = 667–678 | date = January 2004 | pmid = 14687564 | doi = 10.1016/j.jmb.2003.09.082 }}</ref>

====Maintenance of lysogeny====
[[File:Phage Lambda Integration Excision.jpg|thumb|right|upright=1.75|A simplified representation of the integration/excision paradigm and the major genes involved.]]
* Lysogeny is maintained solely by cI. cI represses transcription from ''P<sub>L</sub>'' and ''P<sub>R</sub>'' while upregulating and controlling its own expression from ''P<sub>RM</sub>''. It is therefore the only protein expressed by lysogenic phage.
[[File:Polymerase cl protien.svg|thumb|Lysogen repressors and polymerase bound to OR1 and recruits OR2, which will activate PRM and shutdown PR.]]
* This is coordinated by the ''P<sub>L</sub>'' and ''P<sub>R</sub>'' operators. Both operators have three binding sites for cI: ''OL1'', ''OL2'', and ''OL3'' for ''P<sub>L</sub>'', and ''OR1'', ''OR2'' and ''OR3'' for ''P<sub>R</sub>''.
* cI binds most favorably to ''OR1''; binding here inhibits transcription from ''P<sub>R</sub>''. As cI easily dimerises, the binding of cI to ''OR1'' greatly increases the affinity of the binding of cI to ''OR2'', and this happens almost immediately after ''OR1'' binding. This activates transcription in the other direction from ''P<sub>RM</sub>'', as the N terminal domain of cI on ''OR2'' tightens the binding of RNA polymerase to ''P<sub>RM</sub>'' and hence cI stimulates its own transcription. When it is present at a much higher concentration, it also binds to ''OR3'', inhibiting transcription from ''P<sub>RM</sub>'', thus regulating its own levels in a [[negative feedback]] loop.
* cI binding to the ''P<sub>L</sub>'' operator is very similar, except that it has no direct effect on cI transcription. As an additional repression of its own expression, however, cI dimers bound to ''OR3'' and ''OL3'' bend the DNA between them to tetramerise.
* The presence of cI causes immunity to superinfection by other lambda phages, as it will inhibit their ''P<sub>L</sub>'' and ''P<sub>R</sub>'' promoters.

====Induction====
[[File:Phage Lambda SwitchStates.jpg|thumb|200px|upright=1.5|Transcriptional state of the P<sub>RM</sub> and P<sub>R</sub> promoter regions during a lysogenic state vs induced, early lytic state.]]
The classic induction of a lysogen involved irradiating the infected cells with UV light. Any situation where a lysogen undergoes DNA damage or the [[SOS response]] of the host is otherwise stimulated leads to induction.
# The host cell, containing a dormant phage genome, experiences DNA damage due to a high stress environment, and starts to undergo the [[SOS response]].
# RecA (a cellular protein) detects DNA damage and becomes activated. It is now RecA*, a highly specific co-protease.
# Normally RecA* binds LexA (a [[transcription (genetics)|transcription]] repressor), activating LexA auto-protease activity, which destroys LexA repressor, allowing production of [[DNA repair]] proteins. In lysogenic cells, this response is hijacked, and RecA* stimulates  cI autocleavage. This is because cI mimics the structure of LexA at the autocleavage site.
# Cleaved cI can no longer dimerise, and loses its affinity for DNA binding.
# The ''P<sub>R</sub>'' and ''P<sub>L</sub>'' promoters are no longer repressed and switch on, and the cell returns to the lytic sequence of expression events (note that cII is not stable in cells undergoing the SOS response). There is however one notable difference.
[[File:Lambda phage LexA inihibition.svg|thumb|right|200px|The function of LexA in the SOS response.  LexA expression leads to inhibition of various genes including LexA.]]

====Control of phage genome excision in induction====
# The phage genome is still inserted in the host genome and needs excision for DNA replication to occur. The ''sib'' section beyond the normal ''P<sub>L</sub>'' promoter transcript is, however, no longer included in this reading frame (see diagram).
# No ''sib'' domain on the ''P<sub>L</sub>'' promoter mRNA results in no hairpin loop on the 3' end, and the transcript is no longer targeted for RNAaseIII degradation.
# The new intact transcript has one  copy of both ''xis'' and ''int'', so approximately equal concentrations of xis and int proteins are produced.
# Equal concentrations of xis and int result in the excision of the inserted genome from the host genome for replication and later phage production.