Abstract
Somatic hypermutation of immunoglobulin genes is a highly mutagenic process that is B cell-specific and occurs during antigen-driven responses leading to antigen specificity and antibody affinity maturation. Mutations at the Ig locus are initiated by Activation-Induced cytidine Deaminase and are equally distributed at G/C and A/T bases. This requires the establishment of error-prone repair pathways involving the activity of several low fidelity DNA polymerases. In the physiological context, the G/C base pair mutations involve multiple error-prone DNA polymerases, while the generation of mutations at A/T base pairs depends exclusively on the activity of DNA polymerase η. Using two large cohorts of individuals with xeroderma pigmentosum variant (XP-V), we report that the pattern of mutations at Ig genes becomes highly enriched with large deletions. This observation is more striking for patients older than 50 years. We propose that the absence of Pol η allows the recruitment of other DNA polymerases that profoundly affect the Ig genomic landscape.
Highlights
POLH codes for the DNA polymerase η (Pol η)[7,8], a Y-family DNA polymerase specialized in the translesion synthesis (TLS) of CPDs9, a DNA lesion that blocks replicative polymerases
In cells lacking Pol η, it is admitted that the bypass of CPDs is carried out by other TLS polymerases that are extremely more mutagenic, like pols ζ, κ or ι, which accounts for the occurrence of mutations and for the increased incidence of sun-exposed skin cancers in xeroderma pigmentosum variant (XP-V) patients[10]
Besides its established function in the error-free bypass of UV-induced lesions, Pol η is involved in immunoglobulin (Ig) gene somatic hypermutation (SHM), a unique and highly mutagenic process specific to activated B lymphocytes, which occurs in germinal centers (GC) of secondary lymphoid organs
Summary
POLH codes for the DNA polymerase η (Pol η)[7,8], a Y-family DNA polymerase specialized in the translesion synthesis (TLS) of CPDs9, a DNA lesion that blocks replicative polymerases. Besides its established function in the error-free bypass of UV-induced lesions, Pol η is involved in immunoglobulin (Ig) gene somatic hypermutation (SHM), a unique and highly mutagenic process specific to activated B lymphocytes, which occurs in germinal centers (GC) of secondary lymphoid organs. Using mouse models, we have shown that, in the complete absence of Pol η, mismatch repair-dependent mutations are introduced by one or more DNA polymerases that are not usually involved in SHM. We have shown that at least another DNA polymerase, Pol κ, can be mobilized during SHM in the complete absence of Pol η leading to a new mutational signature. We noticed that, in the absence of Pol η, its substitution by other TLS polymerases leads to a modified landscape of mutations with an increase rate of deletions and insertions, especially in patients older than 50 years
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