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通过耗尽组蛋白伴侣 ASF1 快速诱导端粒的替代性延长。

Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1.

机构信息

Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.

1] Institut Curie, Centre de Recherche, Paris, France. [2] Centre National de la Recherche Scientifique, Paris, France. [3].

出版信息

Nat Struct Mol Biol. 2014 Feb;21(2):167-74. doi: 10.1038/nsmb.2754. Epub 2014 Jan 12.

DOI:10.1038/nsmb.2754
PMID:24413054
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3946341/
Abstract

The mechanism of activation of the alternative lengthening of telomeres (ALT) pathway of mammalian chromosome-end maintenance has been unclear. We have now discovered that co-depletion of the histone chaperones ASF1a and ASF1b in human cells induced all hallmarks of ALT in both primary and cancer cells. These included the formation of ALT-associated PML (promyelocytic leukemia) bodies (APBs), the presence of extrachromosomal telomeric DNA species, an elevated frequency of telomeric sister chromatid exchanges (t-SCE) events and intertelomeric exchange of an integrated tag. The induction of ALT characteristics in this setting led to the simultaneous suppression of telomerase. We determined that ALT induction is positively regulated by the proteins RAD17 and BLM and negatively regulated by EXO1 and DNA2. The induction of ALT phenotypes as a consequence of ASF1 depletion strongly supports the hypothesis that ALT is a consequence of histone management dysfunction.

摘要

哺乳动物染色体末端维持的端粒延长替代途径（ALT）的激活机制尚不清楚。我们现在发现，在人类细胞中同时耗尽组蛋白伴侣 ASF1a 和 ASF1b 会在原代细胞和癌细胞中诱导 ALT 的所有特征。这些特征包括 ALT 相关的早幼粒细胞白血病体（PML）的形成（APBs），存在染色体外端粒 DNA 物种，端粒姐妹染色单体交换（t-SCE）事件的频率升高，以及整合标签的端粒间交换。在这种情况下，ALT 特征的诱导导致端粒酶的同时抑制。我们确定，RAD17 和 BLM 蛋白正向调节 ALT 的诱导，而 EXO1 和 DNA2 负向调节。ASF1 耗竭导致 ALT 表型的诱导强烈支持这样的假设，即 ALT 是组蛋白管理功能障碍的结果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d68/3946341/a72829c86b1e/nihms546127f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d68/3946341/a72829c86b1e/nihms546127f7.jpg

相似文献

[1]
Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1.

Nat Struct Mol Biol. 2014-1-12

[2]
HP1-mediated formation of alternative lengthening of telomeres-associated PML bodies requires HIRA but not ASF1a.

PLoS One. 2011-2-15

[3]
G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells.

Genes (Basel). 2020-3-13

[4]
The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells.

J Cell Sci. 2013-6-26

[5]
Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT).

Cell Death Dis. 2023-2-9

[6]
Telomerase suppresses formation of ALT-associated single-stranded telomeric C-circles.

Mol Cancer Res. 2013-3-15

[7]
WRN loss induces switching of telomerase-independent mechanisms of telomere elongation.

PLoS One. 2014-4-7

[8]
ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity.

PLoS Biol. 2020-1-2

[9]
Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition.

Nucleic Acids Res. 2024-6-24

[10]
Evidence for alternative lengthening of telomeres in liposarcomas in the absence of ALT-associated PML bodies.

Int J Cancer. 2008-6-1

引用本文的文献

[1]
Epitalon increases telomere length in human cell lines through telomerase upregulation or ALT activity.

Biogerontology. 2025-9-4

[2]
Atypical R-loops in cancer: decoding molecular chaos for therapeutic gain.

J Transl Med. 2025-8-14

[3]
Distinct mechanisms underlying extrachromosomal telomere DNA generation in ALT cancers.

Nucleic Acids Res. 2025-8-11

[4]
Conserved and unique features of terminal telomeric sequences in ALT-positive cancer cells.

Elife. 2025-8-1

[5]
TERRA R-loops trigger a switch in telomere maintenance towards break-induced replication and PRIMPOL-dependent repair.

EMBO J. 2025-7-7

[6]
SLX4IP acts in parallel to FANCM to limit BLM-dependent replication stress at ALT telomeres.

bioRxiv. 2025-5-29

[7]
Conserved and Unique Features of Terminal Telomeric Sequences in ALT-Positive Cancer Cells.

bioRxiv. 2025-6-2

[8]
Multiple functions of the ALT favorite helicase, BLM.

Cell Biosci. 2025-3-1

[9]
Elevated reactive oxygen species can drive the alternative lengthening of telomeres pathway in ATRX-null cancers.

Nucleic Acids Res. 2025-2-8

[10]
Identification of modulators of the ALT pathway through a native FISH-based optical screen.

Cell Rep. 2025-1-28

本文引用的文献

[1]
The telomere deprotection response is functionally distinct from the genomic DNA damage response.

Mol Cell. 2013-7-11

[2]
Mammalian DNA2 helicase/nuclease cleaves G-quadruplex DNA and is required for telomere integrity.

EMBO J. 2013-4-19

[3]
Replication stress links structural and numerical cancer chromosomal instability.

Nature. 2013-2-28

[4]
A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells.

Chem Biol. 2013-1-24

[5]
Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells.

J Cell Biol. 2012-12-10

[6]
Loss of wild-type ATRX expression in somatic cell hybrids segregates with activation of Alternative Lengthening of Telomeres.

PLoS One. 2012-11-20

[7]
DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition.

Nature. 2012-10-17

[8]
Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway.

PLoS Genet. 2012-7-19

[9]
RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity.

Cell. 2012-5-11

[10]
The BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures.

Nucleic Acids Res. 2012-5-10

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