POLD1 Deficiency Reveals a Role for POLD1 in DNA Repair and T and B Cell Development

Nichols-Vinueza, Diana; Delmonte, Ottavia M.; Bundy, Vanessa; Bosticardo, Marita; Zimmermann, Michael T.; Dsouza, Nikita R.; Pala, Francesca; Dobbs, Kerry; Stoddard, Jennifer; Niemela, Julie E.; Keller, Michael D.; Rueda, Cesar M.; Abraham, Roshini S.; Urrutia, Raúl; Rosenzweig, Sergio D.; Notarangelo, Luigi D.

doi:10.1007/s10875-020-00903-6

Cited by 14 publications

(16 citation statements)

References 13 publications

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“…POLD1, which provides the essential catalytic activities of Pol δ, plays an important role in DNA synthesis, DNA damage repair, and maintenance of genomic integrity 19 . The downregulation of POLD1 suppressed cell proliferation, DNA synthesis, and DNA damage repair in HEK-293 cells, human fibroblast cells, and immune cells 55,56 . A growing body of studies have implicated the defect of POLD1 in the progression of aging and aging-related diseases.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of KLF14 accelerated cellular senescence and aging

Hou¹,

Qiao²,

Wang

et al. 2023

Preprint

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Aging has been considered as a risk factor in many diseases, thus, comprehensively understanding the cellular and molecular mechanisms of delayed aging is important. Here we investigated whether KLF14 is a suppressor of cellular senescence and aging. In our research, KLF14 levels significantly decreased not only in the serum and lymphocytes of healthy people but also in the cells and tissues of mice with aging. We performed in vitro and in vivo experiments on cells and mice to reveal the function of KLF14 in aging. KLF14 deficiency facilitates cellular senescence and aging-related pathologies in C57BL/6 mice, whereas KLF14 overexpression attenuates cellular senescence. Mechanistically, KLF14 delays aging by binding to the POLD1 promoter to positively regulate POLD1 expression. Remarkably, cellular senescence mediated by KLF14 downregulation could be alleviated by POLD1expression. In addition, perhexiline, an agonist of KLF14, could delay cellular senescence and aging-related pathologies in SAMP8 mice by inducing POLD1 expression, as perhexiline could enhance the effect of KLF14’s transcription activation to POLD1 by elevating the binding level of KLF14 to the POLD1 promoter. Our data indicate that KLF14 might be a critical element in aging by upregulating POLD1 expression, indicating that the activation of KLF14 may delay aging and aging-associated diseases.

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Section: Discussionmentioning

confidence: 99%

Downregulation of KLF14 accelerated cellular senescence and aging

Hou¹,

Qiao²,

Wang

et al. 2023

Preprint

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“…Pathogenic variants in pol δ disrupting POLD1 and POLD2 have also been linked to immunodeficiency, similar to diseases seen with defects in other polymerase subunits ( Figure 10 ) [ 90 , 93 , 94 , 96 , 97 ]. Affected individuals had severe lymphopenia of NK cells and CD4 + T cells, reduced CD8+ T cells, agammaglobulinemia, abnormal distribution of progenitor cells in the bone marrow or B cell lymphopenia [ 108 , 109 , 110 ]. Studies with patient-derived cells demonstrated impaired T cell development and proliferation [ 108 , 109 , 110 ].…”

Section: Diseasesmentioning

confidence: 99%

“…Affected individuals had severe lymphopenia of NK cells and CD4 + T cells, reduced CD8+ T cells, agammaglobulinemia, abnormal distribution of progenitor cells in the bone marrow or B cell lymphopenia [ 108 , 109 , 110 ]. Studies with patient-derived cells demonstrated impaired T cell development and proliferation [ 108 , 109 , 110 ]. T and NK cells exhibited increased spontaneous DNA damage and NK cells were defective in their response to X-ray irradiation [ 109 ].…”

Section: Diseasesmentioning

confidence: 99%

“…Studies with patient-derived cells demonstrated impaired T cell development and proliferation [ 108 , 109 , 110 ]. T and NK cells exhibited increased spontaneous DNA damage and NK cells were defective in their response to X-ray irradiation [ 109 ]. DNA combing of patient fibroblasts showed reduced origin firing with a compensatory increase in fork speed [ 108 ].…”

Section: Diseasesmentioning

confidence: 99%

“…DNA combing of patient fibroblasts showed reduced origin firing with a compensatory increase in fork speed [ 108 ]. Additionally, the S phase checkpoint was activated and an increase in p53 binding protein 1 (53BP1) nuclear bodies was observed in the G1 phase of the cell cycle, indicative of replication stress and under-replicated DNA [ 108 , 109 ]. Additional symptoms included short stature, intellectual disability and hearing loss.…”

Section: Diseasesmentioning

confidence: 99%

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Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms

Schmit

Bielinsky

2021

IJMS

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Deoxyribonucleic acid (DNA) replication can be divided into three major steps: initiation, elongation and termination. Each time a human cell divides, these steps must be reiteratively carried out. Disruption of DNA replication can lead to genomic instability, with the accumulation of point mutations or larger chromosomal anomalies such as rearrangements. While cancer is the most common class of disease associated with genomic instability, several congenital diseases with dysfunctional DNA replication give rise to similar DNA alterations. In this review, we discuss all congenital diseases that arise from pathogenic variants in essential replication genes across the spectrum of aberrant replisome assembly, origin activation and DNA synthesis. For each of these conditions, we describe their clinical phenotypes as well as molecular studies aimed at determining the functional mechanisms of disease, including the assessment of genomic stability. By comparing and contrasting these diseases, we hope to illuminate how the disruption of DNA replication at distinct steps affects human health in a surprisingly cell-type-specific manner.

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