Poletto Mattia, Legrand Arnaud J, Fletcher Sally C, Dianov Grigory L
CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK.
CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Lavrenteva 10, 630090 Novosibirsk, Russia
Nucleic Acids Res. 2016 Apr 20;44(7):3165-75. doi: 10.1093/nar/gkw015. Epub 2016 Jan 14.
DNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these processes are extremely well-coordinated as unrepaired DNA single strand breaks (SSBs) can be converted to DNA double strand breaks during replication thus triggering genomic instability. However, the mechanism(s) governing the BER process are poorly understood. Here we show that accumulation of unrepaired SSBs triggers a p53/Sp1-dependent downregulation of APE1, the endonuclease responsible for the DNA incision during BER. Importantly, we demonstrate that impaired p53 function, a characteristic of many cancers, leads to a failure of the BER coordination mechanism, overexpression of APE1, accumulation of DNA strand breaks and results in genomic instability. Our data provide evidence for a previously unrecognized mechanism for coordination of BER by p53, and its dysfunction in p53-inactivated cells.
由于内源性和外源性诱变剂的作用,DNA不断经历化学修饰。DNA碱基切除修复(BER)途径是处理大多数此类损伤的一线机制,主要涉及DNA切割和随后的重新封闭步骤。至关重要的是,这些过程必须极其协调,因为未修复的DNA单链断裂(SSB)在复制过程中可转化为DNA双链断裂,从而引发基因组不稳定。然而,目前对BER过程的调控机制了解甚少。在此,我们表明未修复的SSB的积累会触发p53/Sp1依赖的APE1下调,APE1是BER过程中负责DNA切割的核酸内切酶。重要的是,我们证明p53功能受损(许多癌症的一个特征)会导致BER协调机制失效、APE1过表达、DNA链断裂积累并导致基因组不稳定。我们的数据为p53协调BER的一种先前未被认识的机制及其在p53失活细胞中的功能障碍提供了证据。