POLD1是抑癌基因，编码蛋白是DNA聚合酶δ复合物P125的催化亚基。p125亚基含有聚合酶和3'-5'的核酸外切酶活性。POLD1参与DNA复制期间的滞后链的DNA合成、聚合期间的校正活性和DNA修复。在功能研究中，POLD1的表达量降低引起DNA复制过程中的误差增加而导致基因组不稳定。此外，POLD1的表达量降低与脆性位点不稳定性和高频率的染色体畸变有关。最近研究表明，随着年龄的增长，POLD1蛋白水平降低，导致DNA修复能力降低。POLD1外切酶结构域的胚系功能缺失突变是导致多种疾病的原因，包括以皮下脂肪营养不良、耳聋、下颌骨发育不全和性腺功能减退为特征的不同的多系统疾病。POLD1的外切核酸酶域杂合胚系突变也使个体易患结直肠癌和子宫内膜癌。此外，POLD1变异与乳腺癌风险也有相关性。

POLD1 encodes an enzyme involved in DNA replication and repair. Germline mutations of POLD1 predispose to colorectal and endometrial cancers. POLD1 is the catalytic subunit of the DNA polymerase δ complex p125. The p125 subunit contains both polymerase and 3ꞌ to 5ꞌ exonuclease activity. POLD1 is involved in DNA synthesis of the lagging strand during DNA replication, proofreading activity during polymerization and DNA repair. In functional studies, reduced expression of POLD1 was shown to cause genomic instability resulting from the accrual of errors during DNA replication. Furthermore, reduced expression of POLD1 was associated with fragile site instability and a high frequency of chromosomal aberrations. Recent studies have demonstrated that levels of POLD1 protein decrease with age, resulting in reduced DNA repair capacity. Germline loss-of-function mutations in the exonuclease domain of POLD1 are responsible for several disorders including the distinct multisystem disorder characterized by subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. Heterozygous germline mutations in the exonuclease domain of POLD1 also predispose individuals to colorectal and endometrial cancers. In addition, associations between POLD1 variants and breast cancer risk have been shown in several studies. POLD1 mutations have been identified as drivers of hypermutation, and therefore, cancers with POLD1 variants may be increasingly sensitive to immunotherapy.

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