Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Department of Microbiology, Kanazawa Medical University, Uchinada Ishikawa, Kanazawa, Japan.
Nat Commun. 2021 Jun 8;12(1):3448. doi: 10.1038/s41467-021-23835-0.
Safeguards against excess DNA replication are often dysregulated in cancer, and driving cancer cells towards over-replication is a promising therapeutic strategy. We determined DNA synthesis patterns in cancer cells undergoing partial genome re-replication due to perturbed regulatory interactions (re-replicating cells). These cells exhibited slow replication, increased frequency of replication initiation events, and a skewed initiation pattern that preferentially reactivated early-replicating origins. Unlike in cells exposed to replication stress, which activated a novel group of hitherto unutilized (dormant) replication origins, the preferred re-replicating origins arose from the same pool of potential origins as those activated during normal growth. Mechanistically, the skewed initiation pattern reflected a disproportionate distribution of pre-replication complexes on distinct regions of licensed chromatin prior to replication. This distinct pattern suggests that circumventing the strong inhibitory interactions that normally prevent excess DNA synthesis can occur via at least two pathways, each activating a distinct set of replication origins.
在癌症中，防止过度 DNA 复制的保护机制常常失调，促使癌细胞过度复制是一种很有前途的治疗策略。我们在因调控相互作用（re-replicating cells）受到干扰而发生部分基因组再复制的癌细胞中确定了 DNA 合成模式。这些细胞表现出缓慢的复制、复制起始事件频率增加以及偏向优先重新激活早期复制起点的起始模式。与暴露于复制应激的细胞不同，复制应激会激活一组以前未利用（休眠）的复制起点，而首选的再复制起点源于与正常生长过程中激活的起点相同的潜在起点池。从机制上讲，这种倾斜的起始模式反映了在复制之前，预复制复合物在已许可染色质的不同区域上的不成比例分布。这种独特的模式表明，至少可以通过两种途径来规避通常阻止过度 DNA 合成的强抑制相互作用，每条途径都激活一组独特的复制起点。
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