Mouse models of DNA polymerases

Menezes, Miriam R.; Sweasy, Joann B.

doi:10.1002/em.21731

Cited by 6 publications

(4 citation statements)

References 226 publications

(192 reference statements)

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“…Based on these and other earlier studies, several knock‐in (KI) Polb mice have been developed that are continually advancing our understanding of the role of Polβ at the organismic level (Menezes & Sweasy, 2012) (Table 2, Figure 3). The first of these KI mice to be reported describes the introduction of the Y265C variant, Polb Y265C (Senejani et al, 2012).…”

Section: Gene Knock‐in Mouse Models For Polβmentioning

confidence: 99%

Mouse models to explore the biological and organismic role of DNA polymerase beta

Sobol

2024

Environ and Mol Mutagen

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Gene knock‐out (KO) mouse models for DNA polymerase beta (Polβ) revealed that loss of Polβ leads to neonatal lethality, highlighting the critical organismic role for this DNA polymerase. While biochemical analysis and gene KO cell lines have confirmed its biochemical role in base excision repair and in TET‐mediated demethylation, more long‐lived mouse models continue to be developed to further define its organismic role. The Polb‐KO mouse was the first of the Cre‐mediated tissue‐specific KO mouse models. This technology was exploited to investigate roles for Polβ in V(D)J recombination (variable‐diversity‐joining rearrangement), DNA demethylation, gene complementation, SPO11‐induced DNA double‐strand break repair, germ cell genome stability, as well as neuronal differentiation, susceptibility to genotoxin‐induced DNA damage, and cancer onset. The revolution in knock‐in (KI) mouse models was made possible by CRISPR/cas9‐mediated gene editing directly in C57BL/6 zygotes. This technology has helped identify phenotypes associated with germline or somatic mutants of Polβ. Such KI mouse models have helped uncover the importance of key Polβ active site residues or specific Polβ enzyme activities, such as the PolbY265C mouse that develops lupus symptoms. More recently, we have used this KI technology to mutate the Polb gene with two codon changes, yielding the PolbL301R/V303R mouse. In this KI mouse model, the expressed Polβ protein cannot bind to its obligate heterodimer partner, Xrcc1. Although the expressed mutant Polβ protein is proteolytically unstable and defective in recruitment to sites of DNA damage, the homozygous PolbL301R/V303R mouse is viable and fertile, yet small in stature. We expect that this and additional targeted mouse models under development are poised to reveal new biological and organismic roles for Polβ.

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Section: Gene Knock‐in Mouse Models For Polβmentioning

confidence: 99%

Mouse models to explore the biological and organismic role of DNA polymerase beta

Sobol

2024

Environ and Mol Mutagen

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“…In humans, Pol l is encoded by the POLM gene, located on chromosome 7 [46,47]. In mice, Pol l is encoded by the Polm gene located on chromosome 11 and encodes a 496 amino acid long protein [48,49], which is functionally identical (79% amino acid identity) to the human counterpart.…”

Section: Dna Polymerase L a Unique Polymerase With Versatile Functionsmentioning

confidence: 99%

20 years of DNA Polymerase μ, the polymerase that still surprises

Ghosh

Raghavan

2021

The FEBS Journal

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DNA polymerases are important enzymes involved in DNA replication and repair. Based on sequence homology, DNA polymerases have been grouped into distinct families, which are A, B, X, and Y. The Pol X family consists of four members: Pol k, l, and b and terminal transferase or TdT. Members of the family X are involved in base excision repair, nonhomologous end joining (NHEJ), and V(D)J recombination. One of the most interesting pol X family members is DNA polymerase l, discovered back in 2000. Subsequent studies established the importance of Pol l as a repair polymerase in NHEJ and its interactions with the other proteins of the NHEJ machinery. Pol l has a number of interesting properties, which sets it apart from the other known DNA polymerases, including its ability to synthesize DNA from an unpaired primer terminus as well in the complete absence of a template strand (terminal transferase activity). Another standout property of Pol l is its reduced ability to discriminate between ribonucleotides and deoxyribonucleotides and its ability to utilize both ribonucleotides and deoxyribonucleotides as substrates during the gap-filling stage of NHEJ. In this review, we provide a brief overview of Pol l in double-strand break repair and the current knowledge on its various functional aspects.

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“…CpGs near mitochondrial polymerase gamma ( POLG) were among the top hits in our LUC analysis in mammalian skin. The Polg D257A/D257A mouse line is a known model of progeria with accelerated mitochondrial point mutations and premature aging phenotypes such as hair loss, graying, spinal curvature, testicular atrophy, decreased bone mass, anemia, weight loss, hearing loss, and premature death 35 . We analyzed a publicly available transcriptomic dataset from the cochlea of 9 month old Polg D257A/D257A mice 36 .…”

Section: Introductionmentioning

confidence: 99%

Divergent age-related methylation patterns in long and short-lived mammals

Haghani

Wang²,

et al. 2022

Preprint

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Age-related changes to cytosine methylation have been extensively characterized across the mammalian family. Some cytosines that are conserved across mammals exhibit age-related methylation changes that are so consistent that they were used to successfully develop cross-species age predictors. In a similar vein, methylation levels of some conserved cytosines correlate highly with species lifespan, leading to the development of highly accurate lifespan predictors. Surprisingly, little to no commonality is found between these two sets of cytosines even though the relationship between aging and lifespan is by most measures linked. We ventured to address this conundrum by first identifying age-related cytosines whose methylation levels change in opposite directions between short and long-lived species. We hypothesized that age-related CpGs that are also associated with species lifespan would tap into biological processes that simultaneously impact aging and lifespan. To this end, we analyzed age-related cytosine methylation patterns in 82 mammalian species. For each CpG, we correlated the intra-species age correlation with maximum lifespan across mammalian species. We refer to this correlation of correlations as Lifespan Uber Correlation (LUC). This approach is unique in incorporating age and species lifespan in a single analysis. We identified 629 CpGs with opposing methylation aging patterns in long and short-lived species. Many of these are found to be near BCL11B, NPTN, and HOXC4 loci. Methylation and transcription analyses of Bcl11b knockout mice indicate that this gene partially regulates the methylation state of LUC CpGs. We developed DNAm age estimators (epigenetic clocks) based on LUC CpGs. These LUC clocks exhibited the expected behavior in benchmark aging interventions such as caloric restriction, growth hormone receptor knockout and high-fat diet. Furthermore, we found that Bcl11b heterozygous knockout mice exhibited an increased epigenetic age in the striatum. Overall, we present a bioinformatics approach that identified CpGs and their associated genes implicated both in aging and lifespan. These cytosines lend themselves to developing epigenetic clocks that are sensitive to perturbations that impact both age and lifespan.

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Mouse models of DNA polymerases

Cited by 6 publications

References 226 publications

Mouse models to explore the biological and organismic role of DNA polymerase beta

Mouse models to explore the biological and organismic role of DNA polymerase beta

20 years of DNA Polymerase μ, the polymerase that still surprises

Divergent age-related methylation patterns in long and short-lived mammals

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