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复制蛋白A可防止采用端粒替代延长机制的细胞中积累单链端粒DNA。

Replication protein A prevents accumulation of single-stranded telomeric DNA in cells that use alternative lengthening of telomeres.

作者信息

Grudic Amra, Jul-Larsen Asne, Haring Stuart J, Wold Marc S, Lønning Per Eystein, Bjerkvig Rolf, Bøe Stig Ove

机构信息

Section of Oncology, Department of Medicine, Haukeland University Hospital.

出版信息

Nucleic Acids Res. 2007;35(21):7267-78. doi: 10.1093/nar/gkm738. Epub 2007 Oct 24.

DOI:10.1093/nar/gkm738
PMID:17959650
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2175364/
Abstract

The activation of a telomere maintenance mechanism is required for cancer development in humans. While most tumors achieve this by expressing the enzyme telomerase, a fraction (5-15%) employs a recombination-based mechanism termed alternative lengthening of telomeres (ALT). Here we show that loss of the single-stranded DNA-binding protein replication protein A (RPA) in human ALT cells, but not in telomerase-positive cells, causes increased exposure of single-stranded G-rich telomeric DNA, cell cycle arrest in G2/M phase, accumulation of single-stranded telomeric DNA within ALT-associated PML bodies (APBs), and formation of telomeric aggregates at the ends of metaphase chromosomes. This study demonstrates differences between ALT cells and telomerase-positive cells in the requirement for RPA in telomere processing and implicates the ALT mechanism in tumor cells as a possible therapeutic target.

摘要

端粒维持机制的激活是人类癌症发展所必需的。虽然大多数肿瘤通过表达端粒酶来实现这一点，但一小部分（5-15%）采用一种基于重组的机制，称为端粒替代延长（ALT）。在这里，我们表明，人ALT细胞中而非端粒酶阳性细胞中单链DNA结合蛋白复制蛋白A（RPA）的缺失，会导致富含G的单链端粒DNA暴露增加、细胞周期在G2/M期停滞、ALT相关的PML小体（APB）内单链端粒DNA积累以及中期染色体末端形成端粒聚集体。这项研究证明了ALT细胞和端粒酶阳性细胞在端粒加工中对RPA需求的差异，并表明肿瘤细胞中的ALT机制可能是一个治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/c9ccf0a641b1/gkm738f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/153b14d2c571/gkm738f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/a189e5ba1f66/gkm738f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/e044000afaf5/gkm738f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/f4074023bdfb/gkm738f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/c0b5408d47e4/gkm738f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/c9ccf0a641b1/gkm738f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/153b14d2c571/gkm738f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/a189e5ba1f66/gkm738f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/e044000afaf5/gkm738f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/f4074023bdfb/gkm738f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/c0b5408d47e4/gkm738f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f462/2175364/c9ccf0a641b1/gkm738f6.jpg

相似文献

[1]
Replication protein A prevents accumulation of single-stranded telomeric DNA in cells that use alternative lengthening of telomeres.

Nucleic Acids Res. 2007

[2]
Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference.

Oncogene. 2007-7-12

[3]
Telomerase suppresses formation of ALT-associated single-stranded telomeric C-circles.

Mol Cancer Res. 2013-3-15

[4]
RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells.

Nat Commun. 2014-10-21

[5]
Alternative lengthening of telomeres in mammalian cells.

Oncogene. 2002-1-21

[6]
Probing PML body function in ALT cells reveals spatiotemporal requirements for telomere recombination.

Proc Natl Acad Sci U S A. 2009-9-15

[7]
Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.

Mol Cell. 2021-3-4

[8]
Telomere recombination requires the MUS81 endonuclease.

Nat Cell Biol. 2009-5

[9]
The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins.

Nat Struct Mol Biol. 2007-7

[10]
Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres.

Genes Dev. 2020-3-26

引用本文的文献

[1]
Conserved and unique features of terminal telomeric sequences in ALT-positive cancer cells.

Elife. 2025-8-1

[2]
Telomere interactions and structural variants in ALT cells revealed with TelSPRITE.

bioRxiv. 2024-11-22

[3]
Conserved and Unique Features of Terminal Telomeric Sequences in ALT-Positive Cancer Cells.

bioRxiv. 2025-6-2

[4]
The single-stranded DNA-binding factor SUB1/PC4 alleviates replication stress at telomeres and is a vulnerability of ALT cancer cells.

Proc Natl Acad Sci U S A. 2025-1-14

[5]
LAP2α orchestrates alternative lengthening of telomeres suppression through telomeric heterochromatin regulation with HDAC1: unveiling a potential therapeutic target.

Cell Death Dis. 2024-10-19

[6]
Telomere Reprogramming and Cellular Metabolism: Is There a Link?

Int J Mol Sci. 2024-9-29

[7]
Survival-Related Genes on Chromosomes 6 and 17 in Medulloblastoma.

Int J Mol Sci. 2024-7-9

[8]
Telomere C-Strand Fill-In Machinery: New Insights into the Human CST-DNA Polymerase Alpha-Primase Structures and Functions.

Subcell Biochem. 2024

[9]
The Molecular Mechanisms and Therapeutic Prospects of Alternative Lengthening of Telomeres (ALT).

Cancers (Basel). 2023-3-23

[10]
TZAP overexpression induces telomere dysfunction and ALT-like activity in ATRX/DAXX-deficient cells.

iScience. 2023-3-14

本文引用的文献

[1]
DNA damage induces alternative lengthening of telomeres (ALT) associated promyelocytic leukemia bodies that preferentially associate with linear telomeric DNA.

Cancer Res. 2007-8-1

[2]
Fission yeast Taz1 and RPA are synergistically required to prevent rapid telomere loss.

Mol Biol Cell. 2007-6

[3]
Xrcc3 and Nbs1 are required for the production of extrachromosomal telomeric circles in human alternative lengthening of telomere cells.

Cancer Res. 2007-2-15

[4]
RPA-like proteins mediate yeast telomere function.

Nat Struct Mol Biol. 2007-3

[5]
Human replication protein A unfolds telomeric G-quadruplexes.

Nucleic Acids Res. 2006

[6]
Vertebrate POT1 restricts G-overhang length and prevents activation of a telomeric DNA damage checkpoint but is dispensable for overhang protection.

Mol Cell Biol. 2006-9

[7]
Themes in ssDNA recognition by telomere-end protection proteins.

Trends Biochem Sci. 2006-9

[8]
Promyelocytic leukemia nuclear bodies are predetermined processing sites for damaged DNA.

J Cell Sci. 2006-8-15

[9]
Linear chromosome maintenance in the absence of essential telomere-capping proteins.

Nat Cell Biol. 2006-7

[10]
Telomerase- and capping-independent yeast survivors with alternate telomere states.

Nat Cell Biol. 2006-7

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