DNA polymerase ζ generates tandem mutations in immunoglobulin variable regions

Saribasak, Huseyin; Maul, Robert W.; Cao, Zheng; Yang, William W.; Schenten, Dominik; Kracker, Sven; Gearhart, Patricia J.

doi:10.1084/jem.20112234

Cited by 44 publications

(45 citation statements)

References 36 publications

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“…In yeast, there is additional evidence that MNMs are created by the activity of DNA polymerase zeta (Pol z), an error-prone translesion polymerase that extends DNA synthesis past mismatches and damage-induced lesions (Sakamoto et al 2007;Stone et al 2012). Pol z is also responsible for MNMs that occur during somatic hypermutation of the variable regions of mouse immunoglobulins (Daly et al 2012;Saribasak et al 2012). These results were established by knocking out Pol z in mutant yeast strains and adult mouse cells, but it has not been possible to knock out Pol z in live mice without destroying their embryonic viability (Bemark et al 2000;Esposito et al 2000;Wittschieben et al 2000).…”

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confidence: 99%

Error-prone polymerase activity causes multinucleotide mutations in humans

2014

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About 2% of human genetic polymorphisms have been hypothesized to arise via multinucleotide mutations (MNMs), complex events that generate SNPs at multiple sites in a single generation. MNMs have the potential to accelerate the pace at which single genes evolve and to confound studies of demography and selection that assume all SNPs arise independently. In this paper, we examine clustered mutations that are segregating in a set of 1092 human genomes, demonstrating that the signature of MNM becomes enriched as large numbers of individuals are sampled. We estimate the percentage of linked SNP pairs that were generated by simultaneous mutation as a function of the distance between affected sites and show that MNMs exhibit a high percentage of transversions relative to transitions, findings that are reproducible in data from multiple sequencing platforms and cannot be attributed to sequencing error. Among tandem mutations that occur simultaneously at adjacent sites, we find an especially skewed distribution of ancestral and derived alleles, with GC ! AA, GA ! TT, and their reverse complements making up 27% of the total. These mutations have been previously shown to dominate the spectrum of the error-prone polymerase Pol z, suggesting that low-fidelity DNA replication by Pol z is at least partly responsible for the MNMs that are segregating in the human population. We develop statistical estimates of MNM prevalence that can be used to correct phylogenetic and population genetic inferences for the presence of complex mutations.

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confidence: 99%

Error-prone polymerase activity causes multinucleotide mutations in humans

2014

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“…Recent studies clearly demonstrated that Polη and Polζ are the major TLPs to introduce SHM (11,12). Although CSR is also initiated by AID-dependent SSB, CSR has several distinct features from SHM such as SSB processing to double strand break (DSB) and joining of appropriate pairs of DSB ends (13,14).…”

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confidence: 99%

Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase

Yousif

Stanlie

Mondal

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced cytidine deaminase (AID) is essential to classswitch recombination (CSR) and somatic hypermutation (SHM) in both V region SHM and S region SHM (s-SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair (BER) complex, is required for CSR. Strikingly, however, UNG deficiency causes augmentation of SHM, suggesting involvement of distinct functions of UNG in SHM and CSR. Here, we show that noncanonical scaffold functions of UNG regulate s-SHM negatively and CSR positively. The s-SHM suppressive function of UNG is attributed to the recruitment of faithful BER components at the cleaved DNA locus, with competition against error-prone polymerases. By contrast, the CSR-promoting function of UNG enhances AID-dependent S-S synapse formation by recruiting p53-binding protein 1 and DNAdependent protein kinase, catalytic subunit. Several loss-of-catalysis mutants of UNG discriminated CSR-promoting activity from s-SHM suppressive activity. Taken together, the noncanonical function of UNG regulates the steps after AID-induced DNA cleavage: errorprone repair suppression in s-SHM and end-joining promotion in CSR.NHEJ | synapsis

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“…Cells can relieve arrest through translesion DNA synthesis (TLS) 5 that provides tolerance to DNA damage (1,2). In processing damaged DNA through this mechanism, a nucleotide opposite the lesion is incorporated to bypass the damage but at the cost of increased rates of mutation (3,4). Unlike classic DNA polymerases, many TLS DNA polymerases are present in most human cells (5,6).…”

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confidence: 99%

“…In addition, a null Rev3 mutation in mouse results in severe early developmental lethality, leaving its function, especially its involvement in various cell lineages, largely unknown (14 -16). A more restricted conditional null mutation of Rev3 in mouse embryonic fibroblast cells and adult B cells documents a need for Pol, without which increased chromosomal aberrations lead to enhanced tumorigenesis (17,18), reduced somatic mutations, and cell proliferation (3,19). Although overexpression of REV7 is associated with high mortality in patients with colon cancer (20), relatively little is known about the role of REV7 and its regulation of Pol function in TLS.…”

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confidence: 99%

A Missense Mutation in Rev7 Disrupts Formation of Polζ, Impairing Mouse Development and Repair of Genotoxic Agent-induced DNA Lesions

Khalaj

Abbasi

Yamanishi

et al. 2014

Journal of Biological Chemistry

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Background: Rev7 encodes a subunit of Pol for translesion DNA synthesis (TLS). Results: We found a Rev7 mutation in mice that causes developmental defects and increases susceptibility for genotoxicity. Conclusion: Rev7 is essential for mouse development through its function in cell proliferation.Significance: These findings demonstrate a unique function of Pol in development that is absent in other TLS polymerases.

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DNA polymerase ζ generates tandem mutations in immunoglobulin variable regions

Abstract: Genetic inactivation of the genes encoding several low-fidelity DNA polymerases indicates that DNA polymerase ζ inserts tandem double-base substitutions in the immunoglobulin variable region in mouse B cells.

Cited by 44 publications

References 36 publications

Error-prone polymerase activity causes multinucleotide mutations in humans

Error-prone polymerase activity causes multinucleotide mutations in humans

Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase

A Missense Mutation in Rev7 Disrupts Formation of Polζ, Impairing Mouse Development and Repair of Genotoxic Agent-induced DNA Lesions

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