Sidorova Julia
Department of Pathology, University of Washington, Seattle, Washington, USA.
Cell Stress. 2017 Dec;1(3):115-133. doi: 10.15698/cst2017.12.114. Epub 2017 Dec 5.
During the hours that human cells spend in the DNA synthesis (S) phase of the cell cycle, they may encounter adversities such as DNA damage or shortage of nucleotides. Under these stresses, replication forks in DNA may experience slowing, stalling, and breakage. Fork remodeling mechanisms, which stabilize slow or stalled replication forks and ensure their ability to continue or resume replication, protect cells from genomic instability and carcinogenesis. Fork remodeling includes DNA strand exchanges that result in annealing of newly synthesized strands (fork reversal), controlled DNA resection, and cleavage of DNA strands. Defects in major tumor suppressor genes BRCA1 and BRCA2, and a subset of the Fanconi Anemia genes have been shown to result in deregulation in fork remodeling, and most prominently, loss of kilobases of nascent DNA from stalled replication forks. This phenomenon has recently gained spotlight as a potential marker and mediator of chemo-sensitivity in cancer cells and, conversely, its suppression - as a hallmark of acquired chemo-resistance. Moreover, nascent strand degradation at forks is now known to also trigger innate immune response to self-DNA. An increasingly sophisticated molecular description of these events now points at a combination of unbalanced fork reversal and end-resection as a root cause, yet also reveals the multi-layered complexity and heterogeneity of the underlying processes in normal and cancer cells.
在人类细胞处于细胞周期的DNA合成（S）期的数小时内，它们可能会遇到诸如DNA损伤或核苷酸短缺等逆境。在这些压力下，DNA中的复制叉可能会经历减慢、停滞和断裂。叉重塑机制可稳定缓慢或停滞的复制叉，并确保其继续或恢复复制的能力，从而保护细胞免受基因组不稳定和癌变的影响。叉重塑包括导致新合成链退火（叉逆转）的DNA链交换、受控的DNA切除以及DNA链的切割。主要肿瘤抑制基因BRCA1和BRCA2以及范可尼贫血基因的一个子集的缺陷已被证明会导致叉重塑失调，最显著的是，停滞的复制叉会丢失数千碱基的新生DNA。这种现象最近作为癌细胞化疗敏感性的潜在标志物和介质受到关注，相反，其抑制——作为获得性化疗耐药的标志。此外，现在已知叉处的新生链降解也会触发对自身DNA的先天免疫反应。对这些事件越来越复杂的分子描述现在指出，不平衡的叉逆转和末端切除的组合是根本原因，但也揭示了正常细胞和癌细胞中潜在过程的多层次复杂性和异质性。
