The Weatherall Institute of Molecular Medicine, Oxford University, Oxford, England, UK.
J Cell Biol. 2013 Apr 1;201(1):33-48. doi: 10.1083/jcb.201208009. Epub 2013 Mar 25.
Defective DNA repair causes Fanconi anemia (FA), a rare childhood cancer-predisposing syndrome. At least 15 genes are known to be mutated in FA; however, their role in DNA repair remains unclear. Here, we show that the FANCJ helicase promotes DNA replication in trans by counteracting fork stalling on replication barriers, such as G4 quadruplex structures. Accordingly, stabilization of G4 quadruplexes in ΔFANCJ cells restricts fork movements, uncouples leading- and lagging-strand synthesis and generates small single-stranded DNA gaps behind the fork. Unexpectedly, we also discovered that FANCJ suppresses heterochromatin spreading by coupling fork movement through replication barriers with maintenance of chromatin structure. We propose that FANCJ plays an essential role in counteracting chromatin compaction associated with unscheduled replication fork stalling and restart, and suppresses tumorigenesis, at least partially, in this replication-specific manner.
DNA 修复缺陷会导致范可尼贫血症（FA），这是一种罕见的儿童期癌症易患综合征。至少有 15 种已知的 FA 基因突变基因；然而，它们在 DNA 修复中的作用仍不清楚。在这里，我们表明 FANCJ 解旋酶通过抵消复制障碍（如 G4 四链体结构）上的叉停顿，在转录中促进 DNA 复制。因此，在 ΔFANCJ 细胞中稳定 G4 四链体限制了叉的运动，解偶联了前导链和滞后链的合成，并在叉的后面产生了小的单链 DNA 缺口。出乎意料的是，我们还发现 FANCJ 通过将复制障碍处的叉运动与染色质结构的维持相结合来抑制异染色质扩散。我们提出，FANCJ 在外源复制叉停滞和重新启动相关的染色质紧缩中发挥着重要作用，并且至少部分地以这种复制特异性的方式抑制肿瘤发生。
