Abstract

DNA replication forks are constantly challenged by DNA lesions induced by endogenous and exogenous sources. DNA damage tolerance mechanisms ensure that DNA replication continues with minimal effects on replication fork elongation either by using specialized DNA polymerases, which have the ability to replicate through the damaged template, or by skipping the damaged DNA, leaving it to be repaired after replication. These mechanisms are evolutionarily conserved in bacteria, yeast, and higher eukaryotes, and are paramount to ensure timely and faithful duplication of the genome. The Primase and DNA-directed Polymerase (PRIMPOL) is a recently discovered enzyme that possesses both primase and polymerase activities. PRIMPOL is emerging as a key player in DNA damage tolerance, particularly in vertebrate and human cells. Here, we review our current understanding of the function of PRIMPOL in DNA damage tolerance by focusing on the structural aspects that define its dual enzymatic activity, as well as on the mechanisms that control its chromatin recruitment and expression levels. We also focus on the latest findings on the mitochondrial and nuclear functions of PRIMPOL and on the impact of loss of these functions on genome stability and cell survival. Defining the function of PRIMPOL in DNA damage tolerance is becoming increasingly important in the context of human disease. In particular, we discuss recent evidence pointing at the PRIMPOL pathway as a novel molecular target to improve cancer cell response to DNA-damaging chemotherapy and as a predictive parameter to stratify patients in personalized cancer therapy.

摘要

DNA 复制叉不断受到由内源性和外源性来源引起的 DNA 损伤的挑战。DNA 损伤耐受机制通过使用能够通过受损模板进行复制的特殊 DNA 聚合酶，或跳过受损 DNA，使其在复制后得到修复，确保 DNA 复制继续进行，对复制叉伸长的影响最小。这些机制在细菌、酵母和高等真核生物中是进化上保守的，并且对于确保及时和忠实地复制基因组至关重要。Primase和 DNA 导向的Pol聚合酶 (PRIMPOL) 是最近发现的一种酶，它同时具有引物酶和聚合酶活性。PRIMPOL 正在成为 DNA 损伤耐受性的关键参与者，特别是在脊椎动物和人类细胞中。在这里，我们通过关注定义其双重酶活性的结构方面以及控制其染色质募集和表达水平的机制来回顾我们目前对 PRIMPOL 在 DNA 损伤耐受中的功能的理解。我们还关注有关 PRIMPOL 线粒体和核功能的最新发现，以及这些功能丧失对基因组稳定性和细胞存活的影响。在人类疾病的背景下，定义 PRIMPOL 在 DNA 损伤耐受中的功能变得越来越重要。特别是，