page_title: POLD1
section_title: Expression and regulation
hierarchical_section_title: POLD1 / Protein / Expression and regulation
caption_attribution_description: English: interaction matrix
context_page_description: The gene polymerase delta 1 encodes the large, POLD1/p125, catalytic subunit of the DNA polymerase delta complex. The Polδ enzyme is responsible for synthesizing the lagging strand of DNA, and has also been implicated in some activities at the leading strand. The POLD1/p125 subunit encodes both DNA polymerizing and exonuclease domains, which provide the protein an important second function in proofreading to ensure replication accuracy during DNA synthesis, and in a number of types of replication-linked DNA repair following DNA damage. Germline mutations impairing activity of POLD1 have been implicated in several types of hereditary cancer, in some sporadic cancers, and in a developmental syndrome of premature aging, Mandibular hypoplasia, Deafness, and Progeroid features and Lipodystrophy. Studies of POLD1 emphasize the importance of maintaining genomic stability to limit tumorigenesis. It is currently unclear whether the enhanced tumorigenesis associated with POLD1 defects is the result of increased base substitutions or due to fork collapse and production of DNA double strand breaks. Recent reviews have addressed important functions of POLD1 and Polδ.
context_section_description: The POLD1/P125 protein is expressed ubiquitously across a panel of human tissues with high levels in the heart and lung tissues. The subcellular localization of POLD1/p125 is predominantly in the nucleus and nucleoplasm.
  A reduction in POLD1/p125 has been observed in senescent human skin fibroblasts and in lymphocytes from an elderly population. POLD1/p125 expression is epigenetically regulated in response to DNA damage. Other studies have also shown that POLD1/p125 expression is regulated by miR-155, p53 and by the long non-coding RNA, PVT1. In the presence of DNA damage or replication stress (UV light, methyl methanesulfonate, hydroxyurea or aphidicolin), the POLD4/p12 subunit is rapidly degraded.  The catalytic activities of p125 are different whether it is in the heterotetramer (Polδ4, with p12) or in the heterotrimer (Polδ3, without p12). The production of the heterotrimer depends on p12 degradation by the E3 ligase RNF8, a protein involved in DSBs repair and possibly homologous recombination (HR). In addition, the E3 ligase CRL4Cdt2 can degrade POLD4/p12 during normal DNA replication and in the presence of DNA damage. POLD4/p12 can also be degraded by the protease µ-calpain, that is involved in calcium-triggered apoptosis.
  POLD1/p125 has a NoDS domain that regulates transport to the nucleolus in response to acidosis.  Nucleolar transport requires a direct interaction between the p50 subunit and the WRN protein. During DNA damage response, WRN moves out of the nucleolus and thereby releases Polδ. POLD1/p125 has also been shown to interact with PDIP46/SKAR and LMO2.
caption: Figure 3. A matrix of established and putative partners for POLD1 extracted from STRING.  (extracted on 03/31/2016[57]). POLD1 is centered (light green box) with red lines indicating its interactions. The light blue boxes represent interactions of the core complex. The light pink boxes represent other putative interactions in DNA repair and replication. Grey lines represent established and putative interactions between the other represented proteins. The network was mapped by using Cytoscape.[58] The interactions represent high- confidence experimental data extracted from BIND, DIP, GRID, HPRD, IntAct, MINT, and PID curated by STRING.[59] The experimental scores are derived from assays on affinity binding and chromatography.
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