Long INterspersed Element class 1 (LINE‐1) elements are a type of abundant retrotransposons active in mammalian genomes. An average human genome contains ~100 retrotransposition‐competent LINE‐1s, whose activity is influenced by the combined action of cellular repressors and activators. TREX1, SAMHD1 and ADAR1 are known LINE‐1 repressors and when mutated cause the autoinflammatory disorder Aicardi‐Goutières syndrome (AGS). Mutations in RNase H2 are the most common cause of AGS, and its activity was proposed to similarly control LINE‐1 retrotransposition. It has therefore been suggested that increased LINE‐1 activity may be the cause of aberrant innate immune activation in AGS. Here, we establish that, contrary to expectations, RNase H2 is required for efficient LINE‐1 retrotransposition. As RNase H1 overexpression partially rescues the defect in RNase H2 null cells, we propose a model in which RNase H2 degrades the LINE‐1 RNA after reverse transcription, allowing retrotransposition to be completed. This also explains how LINE‐1 elements can retrotranspose efficiently without their own RNase H activity. Our findings appear to be at odds with LINE‐1‐derived nucleic acids driving autoinflammation in AGS.
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. Xeroderma pigmentosum (XP) is a rare, autosomal, recessive disease, characterized by photosensitivity, poikiloderma of sunlight-exposed areas appearing in childhood, and characterized by a 1,000-to 10,000-fold increase in the incidence of cancers in sun-exposed regions of the body (melanoma and non-melanoma skin cancers) 1. Classical XP patients harbor mutations in one of the seven XPA to XPG genes 2 , which encode proteins that are part of the Nucleotide Excision Repair (NER) pathway involved in the removal of UV-induced cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4 PPs) 3. In contrast, patients with the XP variant (XP-V) form retain a normal NER pathway but carry on inactivating bi-allelic mutations in the POLH gene. XP-V patients (OMIM: 278750) account for approximately 20% of all XP patients worldwide. They exhibit some photosensitivity, usually after the age of 15, and may develop multiple skin carcinomas and melanomas with age. XP-V patients have milder and distinct clinical presentations compared to those found in the other XP complementation groups. In particular, they are characterized by: (i) a delayed cancer onset with tumors appearing in 20-30 years old individuals; (ii) variable severity, and (iii) lack of neurologic abnormalities 4-6. POLH codes for the DNA polymerase η (Pol η) 7,8 , a Y-family DNA polymerase specialized in the translesion synthesis (TLS) of CPDs 9 , a DNA lesion that blocks replicative polymerases. Following replication fork stalling, Pol η binds CPD-containing DNA with higher affinity than undamaged DNA, and incorporates dAMP efficiently past cis-syn thymine-thymine dimers 10. 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 (zeta), κ (kappa) or ι (iota), which accounts for the occurrence of mutations and consequently for the increased incidence of sun-exposed skin cancers in XP-V patients 10. Indeed, the analysis of soma...
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