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HLTF 解决 G4s 并促进 G4 诱导的复制叉减速以维持基因组稳定性。

HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability.

机构信息

Department of Chemical & Systems Biology, Stanford University, Stanford, CA 94305, USA.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.

出版信息

Mol Cell. 2024 Aug 22;84(16):3044-3060.e11. doi: 10.1016/j.molcel.2024.07.018. Epub 2024 Aug 13.

DOI:10.1016/j.molcel.2024.07.018
PMID:39142279
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11366124/
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

四链体（G4s）在整个基因组中形成，并影响重要的细胞过程。它们的失调会挑战 DNA 复制叉的进展，并威胁基因组的稳定性。在这里，我们展示了双链 DNA（dsDNA）易位酶解旋酶样转录因子（HLTF）在应对 G4s 方面的意外作用。我们表明，HLTF 在人类基因组中的 G4s 中富集，能够在体外直接展开 G4s，并利用这种依赖 ATP 的易位功能抑制整个细胞周期中 G4 的积累。此外，MSH2（与 G4 结合的 MutS 异二聚体的一个组成部分）和 HLTF 协同作用以抑制 G4 的积累，限制端粒的替代性延长，并促进对 G4 稳定药物的抗性。HLTF 以一种离散但互补的作用发挥作用，当 G4s 通过抑制引物酶-聚合酶（PrimPol）依赖性重新引发而稳定时，它会抑制 DNA 合成。HLTF 在 G4 反应中的这些不同作用共同防止 DNA 损伤和潜在的诱变复制，以保护基因组的稳定性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0c0/11366124/53d9001d12ab/nihms-2017257-f0008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0c0/11366124/53d9001d12ab/nihms-2017257-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0c0/11366124/a24b0d1b1ff9/nihms-2017257-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0c0/11366124/8f2199162f58/nihms-2017257-f0003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0c0/11366124/b16d4664a5df/nihms-2017257-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0c0/11366124/31f50fb3dfed/nihms-2017257-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0c0/11366124/a59942d761ec/nihms-2017257-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0c0/11366124/53d9001d12ab/nihms-2017257-f0008.jpg

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