DNA polymerase η is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse

DNA polymerases in adaptive immunity

“…Accordingly, the reduction in A/T mutagenesis corresponds well with the lower mutagenicity of Polκ 61,62 . Altogether these data support the proposition that Polη is the sole contributor of A/T mutations during physiological SHM in mice, with other TLS polymerases playing a backup role 65 .…”

“…For a long time, no comprehensive explanation was provided for this complex phenotype, which was described before the discovery of AID. However, when compared to the footprint of AID targeting revealed in Ung -/-Msh2 -/-mice, this profile can be simply explained by an increased error-free repair mediated by UNG in the absence of MSH2-MSH6, thus reducing the overall number of mutations 65 . Inefficient displacement of AID from its target DNA would explain the increase in G/C transition mutations (uracils being carried over to replication), especially at a few hotspot positions showing a symmetrical WGCW structure (W standing for A or T).…”

“…The residual A/T mutagenesis appears to be generated by an error-prone repair mobilizing UNG and Polη, as clearly shown by the complete absence of A/T mutations in MSH2/Polη double-deficient mice 65 (Fig.4), but whether this UNG-mediated error-prone repair is artificially caused by the absence of MSH2 is an open question.…”

“…We apologize to those whose work could not be and Ung -/-cells were obtained from Rada et al 98 , all other data are taken from Delbos et al 65 .…”

Hypermutation des gènes des immunoglobulines et polymérases mutagènes

“…D'autres données laissent également penser qu'au moins une partie des mécanismes d'organisation devait déjà être présente avant l'apparition des chordés. En effet, chez les hémichordés, l'un des phylums le plus proche des chordés et qui partage avec eux la présence de structures typiquement induites par l'organisateur telles que les fentes branchiales, le mésoderme du pharynx ou l'endostyle, on observe déjà une expression dorso-ventrale de BMP et de ses antagonistes (par exemple, la chordine) mais de manière inversée par rapport aux chordés [8]. Chez les protostomiens, tels que la drosophile, les orthologues de BMP/Chordine sont aussi exprimés dans l'axe D/V des embryons avec une orientation similaire à celle qui prévaut chez les hémichordés [9].…”