Dataset Information

Pol? tumor variants decrease the efficiency and accuracy of NHEJ.

ABSTRACT: The non homologous end-joining (NHEJ) pathway of double-strand break (DSB) repair often requires DNA synthesis to fill the gaps generated upon alignment of the broken ends, a complex task performed in human cells by two specialized DNA polymerases, Pol? and Pol?. It is now well established that Pol? is the one adapted to repair DSBs with non-complementary ends, the most challenging scenario, although the structural basis and physiological implications of this adaptation are not fully understood. Here, we demonstrate that two human Pol? point mutations, G174S and R175H, previously identified in two different tumor samples and affecting two adjacent residues, limit the efficiency of accurate NHEJ by Pol? in vitro and in vivo. Moreover, we show that this limitation is the consequence of a decreased template dependency during NHEJ, which renders the error-rate of the mutants higher due to the ability of Pol? to randomly incorporate nucleotides at DSBs. These results highlight the relevance of the 8 kDa domain of Pol? for accurate and efficient NHEJ, but also its contribution to the error-prone behavior of Pol? at 2-nt gaps. This work provides the first demonstration that mutations affecting Pol? identified in tumors can alter the efficiency and fidelity of NHEJ.

SUBMITTER: Sastre-Moreno G

PROVIDER: S-EPMC5622330 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Polμ tumor variants decrease the efficiency and accuracy of NHEJ.

Sastre-Moreno Guillermo G Pryor John M JM Díaz-Talavera Alberto A Ruiz José F JF Ramsden Dale A DA Blanco Luis L

Nucleic acids research 20170901 17

The non homologous end-joining (NHEJ) pathway of double-strand break (DSB) repair often requires DNA synthesis to fill the gaps generated upon alignment of the broken ends, a complex task performed in human cells by two specialized DNA polymerases, Polλ and Polμ. It is now well established that Polμ is the one adapted to repair DSBs with non-complementary ends, the most challenging scenario, although the structural basis and physiological implications of this adaptation are not fully understood. ...[more]

PMID: 28973441

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Project description:BackgroundSharing individual phenotype and genotype data between countries is complex and fraught with potential errors, while sharing summary statistics of genome-wide association studies (GWAS) is relatively straightforward, and thus would be especially useful for traits that are expensive or difficult-to-measure, such as feed efficiency. Here we examined: (1) the sharing of individual cow data from international partners; and (2) the use of sequence variants selected from GWAS of international cow data to evaluate the accuracy of genomic estimated breeding values (GEBV) for residual feed intake (RFI) in Australian cows.ResultsGEBV for RFI were estimated using genomic best linear unbiased prediction (GBLUP) with 50k or high-density single nucleotide polymorphisms (SNPs), from a training population of 3797 individuals in univariate to trivariate analyses where the three traits were RFI phenotypes calculated using 584 Australian lactating cows (AUSc), 824 growing heifers (AUSh), and 2526 international lactating cows (OVE). Accuracies of GEBV in AUSc were evaluated by either cohort-by-birth-year or fourfold random cross-validations. GEBV of AUSc were also predicted using only the AUS training population with a weighted genomic relationship matrix constructed with SNPs from the 50k array and sequence variants selected from a meta-GWAS that included only international datasets. The genomic heritabilities estimated using the AUSc, OVE and AUSh datasets were moderate, ranging from 0.20 to 0.36. The genetic correlations (rg) of traits between heifers and cows ranged from 0.30 to 0.95 but were associated with large standard errors. The mean accuracies of GEBV in Australian cows were up to 0.32 and almost doubled when either overseas cows, or both overseas cows and AUS heifers were included in the training population. They also increased when selected sequence variants were combined with 50k SNPs, but with a smaller relative increase.ConclusionsThe accuracy of RFI GEBV increased when international data were used or when selected sequence variants were combined with 50k SNP array data. This suggests that if direct sharing of data is not feasible, a meta-analysis of summary GWAS statistics could provide selected SNPs for custom panels to use in genomic selection programs. However, since this finding is based on a small cross-validation study, confirmation through a larger study is recommended.

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Pol? tumor variants decrease the efficiency and accuracy of NHEJ.

Publications

Polμ tumor variants decrease the efficiency and accuracy of NHEJ.

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