POLD1 (DNA Polymerase Delta 1) is the catalytic subunit of DNA polymerase δ, the primary polymerase responsible for lagging strand DNA synthesis during genome replication and a key enzyme in DNA repair pathways including base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR)[1]. POLD1 is essential for maintaining genomic stability, and its dysfunction has been strongly implicated in neurodegenerative diseases, cancer predisposition, and accelerated aging[2].
DNA polymerase δ is a heterotrimer consisting of POLD1 (catalytic subunit), POLD2 (regulatory subunit), and POLD3 (accessory subunit). The enzyme requires PCNA (proliferating cell nuclear antigen) for processive DNA synthesis and performs both leading and lagging strand synthesis with high fidelity[3].
POLD1 possesses multiple enzymatic functions essential for genome stability:
POLD1's catalytic activities are mediated by conserved domains:
POLD1 dysfunction significantly contributes to Alzheimer's disease pathogenesis:
DNA Damage Accumulation: Impaired POLD1 activity leads to accumulation of DNA damage in neurons, accelerating neurodegeneration[4]. Neuronal DNA damage is a hallmark of AD brains, and POLD1 deficiency compounds this effect.
Genomic Instability: POLD1 deficiency promotes chromosomal instability that may contribute to tau pathology and neuronal dysfunction. Studies show elevated DNA double-strand breaks in AD neurons with reduced POLD1 expression.
Amyloid-β Interaction: Amyloid-β deposition is associated with impaired DNA repair machinery, including reduced POLD1 activity. The relationship creates a vicious cycle where Aβ promotes DNA damage while impaired POLD1 accelerates Aβ-induced toxicity.
Mitochondrial Dysfunction: POLD1 mutations affect mitochondrial DNA replication and repair, compounding mitochondrial dysfunction in AD. Mitochondrial DNA is particularly vulnerable to oxidative damage in AD.
Synaptic Dysfunction: POLD1 plays critical roles in maintaining synaptic DNA integrity, and its dysfunction contributes to synaptic loss in AD[5].
In Parkinson's disease, POLD1 plays a protective role in dopaminergic neurons:
Dopaminergic Neuron Survival: POLD1 activity is crucial for maintaining genomic integrity in dopaminergic neurons, which are particularly vulnerable to oxidative stress[6].
α-Synuclein Interactions: DNA damage can promote α-synuclein aggregation, and POLD1 dysfunction may accelerate this process. Oxidative stress from mitochondrial dysfunction creates DNA damage that impairs POLD1.
Mitochondrial DNA Repair: POLD1 deficiency in mitochondria promotes accumulation of mitochondrial DNA mutations in dopaminergic neurons[7]. This is particularly relevant given the central role of mitochondrial dysfunction in PD.
LRRK2 Connection: POLD1 interacts with LRRK2 pathways, and LRRK2 mutations may affect DNA repair capacity in dopaminergic neurons.
POLD1 involvement in ALS includes:
Motor Neuron Vulnerability: POLD1 dysfunction exacerbates DNA damage accumulation in motor neurons. Motor neurons have high metabolic demands and are particularly sensitive to DNA repair defects.
Oxidative Stress: The high metabolic demand of motor neurons makes them particularly sensitive to POLD1 deficiency under oxidative stress conditions[8].
RNA Processing: POLD1's role in processing R-loops may affect RNA metabolism relevant to TDP-43 pathology in ALS.
C9orf72 Connection: POLD1 dysfunction may interact with C9orf72 repeat expansion toxicity in ALS/FTD.
POLD1 sits at the nexus of DNA damage response and neurodegeneration:
POLD1 mutations cause cancer predisposition syndromes:
POLD1-based therapeutic strategies include:
Key research areas include:
Maga G, et al. DNA polymerase delta: structure, function and role in DNA replication and repair. 2020. ↩︎
Lao VV, et al. POLD1 mutations and polymerase delta in cancer. 2019. ↩︎ ↩︎
Liu L, et al. Structure of the DNA polymerase delta from S. cerevisiae. 2018. ↩︎
Zhou X, et al. DNA polymerase delta dysfunction in Alzheimer disease. 2021. ↩︎
Kim J, et al. DNA polymerase delta in synaptic function. 2022. ↩︎
Chen Y, et al. POLD1 and dopaminergic neuron survival in Parkinson disease. 2022. ↩︎
Zheng W, et al. Mitochondrial DNA polymerase delta in neurodegeneration. 2020. ↩︎
Lee H, et al. Oxidative stress and POLD1 activity in neurons. 2021. ↩︎
Brown KD, et al. Targeting DNA polymerases in therapeutic strategies. 2022. ↩︎