Abstract
POLD1, the catalytic subunit of DNA polymerase δ, plays a critical role in DNA synthesis and DNA repair processes. Moreover, POLD1 is downregulated in replicative senescence to mediate aging. In any case, the components of age-related downregulation of POLD1 expression have not been fully explained. In this article, we elucidate the mechanism of the regulation of POLD1 at the transcription level and found that the transcription factor CCCTC-binding factor (CTCF) was bound to the POLD1 promoter area in two sites. The binding level of CTCF for the POLD1 promoter appeared to be related to aging and was confirmed to be positively controlled by the CTCF level. Additionally, cell senescence characteristics were detected within the cells transfected with short hairpin RNA (shRNA)-CTCF, pLenti-CMV-CTCF, shRNA-POLD1, and pLenti-CMV-POLD1, and the results showed that the CTCF may contribute to the altered expression of POLD1 in aging. In conclusion, the binding level of CTCF for the POLD1 promoter intervened by an age-related decrease in CTCF and downregulated the POLD1 expression in aging. Moreover, the decrease in CTCF-mediated POLD1 transcription accelerates the progression of cell aging.
Highlights
Aging is the major risk factor for most chronic diseases that account for the bulk of morbidity, mortality, and health costs in developed and developing countries (Harper, 2014; Childs et al, 2015; Kirkland and Tchkonia, 2017)
Potential specific CCCTC-binding factor (CTCF)-binding sites were analyzed with the assistance of the JASPAR database, and the results showed five potential CTCF-binding sites in the promoter of POLD1 with a higher score (Figure 1B)
To directly determine which site CTCF binds to the POLD1 promoter, chromatin immunoprecipitation (ChIP)-qPCR assays were performed in lymphocyte cells
Summary
Aging is the major risk factor for most chronic diseases that account for the bulk of morbidity, mortality, and health costs in developed and developing countries (Harper, 2014; Childs et al, 2015; Kirkland and Tchkonia, 2017). POLD1, as the catalytic subunit of DNA polymerase delta and endowed with polymerase and exonuclease activities, plays a critical role in DNA synthesis and DNA repair processes (Cui et al, 2019). Our previous study found that POLD1 expression was downregulated as cell aging in human lymphocytes and preliminarily confirmed that the expression of POLD1 was essential in cell cycle regulation and DNA damage repair processes (Wang et al, 2012; Song et al, 2015; Maierhofer et al, 2019). The mechanism of age-related downregulation of POLD1 expression has not been fully explained
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