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HLTF Promotes Fork Reversal, Limiting Replication Stress Resistance and Preventing Multiple Mechanisms of Unrestrained DNA Synthesis.
Molecular Cell ( IF 16.0 ) Pub Date : 2020-05-21 , DOI: 10.1016/j.molcel.2020.04.031
Gongshi Bai 1 , Chames Kermi 1 , Henriette Stoy 2 , Carl J Schiltz 3 , Julien Bacal 1 , Angela M Zaino 4 , M Kyle Hadden 4 , Brandt F Eichman 3 , Massimo Lopes 2 , Karlene A Cimprich 1
Affiliation  

DNA replication stress can stall replication forks, leading to genome instability. DNA damage tolerance pathways assist fork progression, promoting replication fork reversal, translesion DNA synthesis (TLS), and repriming. In the absence of the fork remodeler HLTF, forks fail to slow following replication stress, but underlying mechanisms and cellular consequences remain elusive. Here, we demonstrate that HLTF-deficient cells fail to undergo fork reversal in vivo and rely on the primase-polymerase PRIMPOL for repriming, unrestrained replication, and S phase progression upon limiting nucleotide levels. By contrast, in an HLTF-HIRAN mutant, unrestrained replication relies on the TLS protein REV1. Importantly, HLTF-deficient cells also exhibit reduced double-strand break (DSB) formation and increased survival upon replication stress. Our findings suggest that HLTF promotes fork remodeling, preventing other mechanisms of replication stress tolerance in cancer cells. This remarkable plasticity of the replication fork may determine the outcome of replication stress in terms of genome integrity, tumorigenesis, and response to chemotherapy.



中文翻译:

HLTF 促进分叉逆转,限制复制应激抵抗并防止无限制 DNA 合成的多种机制。

DNA 复制压力会使复制叉停滞,导致基因组不稳定。DNA 损伤耐受途径有助于叉进展、促进复制叉逆转、跨损伤 DNA 合成 (TLS) 和重新启动。在没有叉重塑剂 HLTF 的情况下,叉在复制压力后无法减慢速度,但潜在的机制和细胞后果仍然难以捉摸。在这里,我们证明 HLTF 缺陷细胞无法在体内进行叉逆转并依靠 primase-polymerase PRIMPOL 进行再启动、无限制复制和限制核苷酸水平的 S 期进展。相比之下,在 HLTF-HIRAN 突变体中,不受限制的复制依赖于 TLS 蛋白 REV1。重要的是,HLTF 缺陷细胞还表现出双链断裂 (DSB) 形成减少和复制压力下存活率增加。我们的研究结果表明 HLTF 促进叉重塑,阻止癌细胞中复制应激耐受的其他机制。复制叉的这种显着可塑性可能决定复制压力在基因组完整性、肿瘤发生和化疗反应方面的结果。

更新日期:2020-06-18
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