Polβ modulates the expression of type I interferon via STING pathway

Huang, Miaoling; Wu, Ting; Li, Rui; Wang, Meina; Shi, Munan; Xin, Jingyu; Shao, Shan; Zhao, Xingqi; Ma, Ying; Gu, Lili; Guo, Zhigang; Pan, Feiyan

doi:10.1016/j.bbrc.2022.07.005

Cited by 6 publications

(7 citation statements)

References 35 publications

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“…Of note, our results may conflict with the traditional understanding of a proficient BER safeguarding against mutation accumulation and tumorigenesis. It should be noted that if the POLB was not mutated, the POLB’s preservation of genomic integrity may remain consistent in either normal cells or tumor cells [ 39 ]. Hence, under normal physiological conditions, POLB aids in the identification of damaged DNA fragments by normal cells, thereby initiating the DNA repair process to avert genomic instability.…”

Section: Discussionmentioning

confidence: 99%

DNA polymerase beta connects tumorigenicity with the circadian clock in liver cancer through the epigenetic demethylation of Per1

Chen,

Zhang,

et al. 2024

Cell Death Dis

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The circadian-controlled DNA repair exhibits a strong diurnal rhythm. Disruption in circadian clock and DNA repair is closely linked with hepatocellular carcinoma (HCC) progression, but the mechanism remains unknown. Here, we show that polymerase beta (POLB), a critical enzyme in the DNA base excision repair pathway, is rhythmically expressed at the translational level in mouse livers. Hepatic POLB dysfunction dampens clock homeostasis, whereas retards HCC progression, by mediating the methylation of the 4th CpG island on the 5′UTR of clock gene Per1. Clinically, POLB is overexpressed in human HCC samples and positively associated with poor prognosis. Furthermore, the hepatic rhythmicity of POLB protein expression is orchestrated by Calreticulin (CALR). Our findings provide important insights into the molecular mechanism underlying the synergy between clock and food signals on the POLB-driven BER system and reveal new clock-dependent carcinogenetic effects of POLB. Therefore, chronobiological modulation of POLB may help to promote precise interventions for HCC.

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Section: Discussionmentioning

confidence: 99%

DNA polymerase beta connects tumorigenicity with the circadian clock in liver cancer through the epigenetic demethylation of Per1

Chen,

Zhang,

et al. 2024

Cell Death Dis

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“…Decreases in the extent of somatic instability in some tissues Lokanga et al (2015) Polb(L22P) Chronic inflammation, stomach tumors, an increase in DNA double strand breaks in stomach cells Polb(L22P) Enhanced Helicobacter pylori induced tumor incidence, an increase in reactive oxygen and nitrogen species-mediated DNA damage mutant is reported to be defective only in 5 0 dRP lyase activity (Dalal et al, 2008) whereas the R137Q Polβ mutant is shown to have decreased DNA polymerase activity, and is impaired for overall BER capacity (Guo et al, 2009). In the mice, the R137Q Polβ mutant embryos are notably smaller and show high mortality (Pan et al, 2016) and the R137Q Polβ mutant mice exhibit an increase in chronic inflammation in multiple organs (Huang et al, 2022). Similarly, the L22P Polβ mutant mice exhibit chronic inflammation accompanied by stomach tumors and an increase in DNA DSBs in stomach cells .…”

Section: Gene Knock-in Mouse Models For Polβmentioning

confidence: 99%

“…In recent studies, mouse models expressing two additional cancer mutants of Polβ have been developed, one targeted to express the L22P Polβ mutant (Zhao, Klattenhoff, et al, 2019; Zhao, Thakur, et al, 2019) and the other to express the R137Q Polβ mutant (Huang et al, 2022; Pan et al, 2016) (Table 2, Figure 3). The L22P Polβ cancer mutant is reported to be defective only in 5′dRP lyase activity (Dalal et al, 2008) whereas the R137Q Polβ mutant is shown to have decreased DNA polymerase activity, and is impaired for overall BER capacity (Guo et al, 2009).…”

Section: Gene Knock‐in Mouse Models For Polβmentioning

confidence: 99%

“…The L22P Polβ cancer mutant is reported to be defective only in 5′dRP lyase activity (Dalal et al, 2008) whereas the R137Q Polβ mutant is shown to have decreased DNA polymerase activity, and is impaired for overall BER capacity (Guo et al, 2009). In the mice, the R137Q Polβ mutant embryos are notably smaller and show high mortality (Pan et al, 2016) and the R137Q Polβ mutant mice exhibit an increase in chronic inflammation in multiple organs (Huang et al, 2022). Similarly, the L22P Polβ mutant mice exhibit chronic inflammation accompanied by stomach tumors and an increase in DNA DSBs in stomach cells (Zhao, Klattenhoff, et al, 2019).…”

Section: Gene Knock‐in Mouse Models For Polβmentioning

confidence: 99%

“…In recent studies, mouse models expressing two additional cancer mutants of Polβ have been developed, one targeted to express the L22P Polβ mutant and the other to express the R137Q Polβ mutant (Huang et al, 2022;Pan et al, 2016) (Table 2, Figure 3). The L22P Polβ cancer T A B L E 2 Polb-knock-in mouse models.…”

Section: Gene Knock-in Mouse Models For Polβmentioning

confidence: 99%

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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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