PDF(Pubmed)
Abstract：
G-quadruplexes (G4s) form throughout the genome and influence important cellular processes. Their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected role for the double-stranded DNA (dsDNA) translocase helicase-like transcription factor (HLTF) in responding to G4s. We show that HLTF, which is enriched at G4s in the human genome, can directly unfold G4s in vitro and uses this ATP-dependent translocase function to suppress G4 accumulation throughout the cell cycle. Additionally, MSH2 (a component of MutS heterodimers that bind G4s) and HLTF act synergistically to suppress G4 accumulation, restrict alternative lengthening of telomeres, and promote resistance to G4-stabilizing drugs. In a discrete but complementary role, HLTF restrains DNA synthesis when G4s are stabilized by suppressing primase-polymerase (PrimPol)-dependent repriming. Together, the distinct roles of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability.
摘要：
G-四链体(G4s)在整个基因组中形成并影响重要的细胞过程。它们的失调可以挑战DNA复制叉进展并威胁基因组稳定性。这里,我们证明了双链DNA（dsDNA）转位酶解旋酶样转录因子（HLTF）在响应G4s中的意想不到的作用。我们证明了HLTF，在人类基因组中富含G4s，可以在体外直接展开G4s，并使用这种ATP依赖性转位酶功能来抑制G4在整个细胞周期中的积累。此外,MSH2（结合G4s的MutS异源二聚体的组成部分）和HLTF协同作用以抑制G4积累，限制端粒的替代延长，并促进对G4稳定药物的耐药性。在离散但互补的角色中，当G4s通过抑制引发酶-聚合酶（PrimPol）依赖性的重新引发而稳定时，HLTF会抑制DNA合成。一起,HLTF在G4反应中的独特作用可防止DNA损伤和潜在的诱变复制,从而保护基因组稳定性.
