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FANCD2在端粒延长替代途径中限制了依赖BLM的端粒不稳定性。

FANCD2 limits BLM-dependent telomere instability in the alternative lengthening of telomeres pathway.

作者信息

Root Heather, Larsen Andrew, Komosa Martin, Al-Azri Fakhriya, Li Ren, Bazett-Jones David P, Stephen Meyn M

机构信息

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto M5G 0A4, Canada.

School of Earth and Space Exploration, Arizona State University, Tempe 85281, USA.

出版信息

Hum Mol Genet. 2016 Aug 1;25(15):3255-3268. doi: 10.1093/hmg/ddw175. Epub 2016 Jul 17.


DOI:10.1093/hmg/ddw175
PMID:27427384
Abstract

Fanconi anemia and Bloom syndrome are genomic instability syndromes caused by mutations in proteins that participate in overlapping DNA repair and replication pathways. Here, we show that the monoubiquitinated form of the Fanconi Anemia protein FANCD2 acts in opposition to the BLM DNA helicase to restrain telomere replication and recombination in human cells that utilize the Alternative Lengthening of Telomeres (ALT) pathway. ALT relies on exchanges of telomeric DNA to maintain telomeres, a process that we show FANCD2 suppresses. Depletion of FANCD2 results in a hyper-ALT phenotype, including an increase in extrachromosomal telomeric repeat DNAs, putative recombinational byproducts that we show exist as intertwined complexes forming the nucleic acid component of ALT-associated PML bodies. Increases in telomeric DNA are suppressed by loss of BLM but not RAD51, occur without parallel upregulation of shelterin proteins TRF1 and TRF2, and are associated with increased frequencies of deprotected and fragile telomeres. Inactivation of the FA pathway does not trigger ALT, as FANCD2 depleted telomerase positive cells do not acquire ALT-like phenotypes. We observe frequent fragile telomeres in ALT cells, suggesting that telomere sequences are prone to replication problems. We propose that, in ALT cells, FANCD2 promotes intramolecular resolution of stalled replication forks in telomeric DNA while BLM facilitates their resection and subsequent involvement in the intermolecular exchanges that drive ALT.

摘要

范可尼贫血和布卢姆综合征是由参与重叠DNA修复和复制途径的蛋白质发生突变引起的基因组不稳定综合征。在这里,我们表明范可尼贫血蛋白FANCD2的单泛素化形式与BLM DNA解旋酶起相反作用,以抑制利用端粒替代延长(ALT)途径的人类细胞中的端粒复制和重组。ALT依赖于端粒DNA的交换来维持端粒,我们发现FANCD2抑制了这一过程。FANCD2的缺失导致高ALT表型,包括染色体外端粒重复DNA增加,我们发现这些假定的重组副产物以相互缠绕的复合物形式存在,构成了ALT相关PML小体的核酸成分。端粒DNA的增加被BLM的缺失所抑制,但不被RAD51抑制,在没有端粒保护蛋白TRF1和TRF2平行上调的情况下发生,并且与去保护和脆弱端粒的频率增加相关。FA途径的失活不会触发ALT,因为FANCD2缺失的端粒酶阳性细胞不会获得ALT样表型。我们在ALT细胞中观察到频繁的脆弱端粒,这表明端粒序列容易出现复制问题。我们提出,在ALT细胞中,FANCD2促进端粒DNA中停滞复制叉的分子内解析,而BLM促进其切除并随后参与驱动ALT的分子间交换。

相似文献

[1]
FANCD2 limits BLM-dependent telomere instability in the alternative lengthening of telomeres pathway.

Hum Mol Genet. 2016-8-1

[2]
A role for monoubiquitinated FANCD2 at telomeres in ALT cells.

Nucleic Acids Res. 2009-4

[3]
FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops.

Sci Rep. 2019-12-13

[4]
Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.

Mol Cell. 2021-3-4

[5]
FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres.

Proc Natl Acad Sci U S A. 2017-7-3

[6]
Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway.

Sci Adv. 2019-10-9

[7]
The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis.

Hum Mol Genet. 2002-12-1

[8]
FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops.

Nat Commun. 2019-5-28

[9]
BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response.

Mol Cell. 2024-5-2

[10]
WRN loss induces switching of telomerase-independent mechanisms of telomere elongation.

PLoS One. 2014-4-7

引用本文的文献

[1]
SLX4IP acts in parallel to FANCM to limit BLM-dependent replication stress at ALT telomeres.

bioRxiv. 2025-5-29

[2]
Multiple functions of the ALT favorite helicase, BLM.

Cell Biosci. 2025-3-1

[3]
Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition.

Nucleic Acids Res. 2024-6-24

[4]
Modified iPOND revealed the role of mutant p53 in promoting helicase function and telomere maintenance.

Aging (Albany NY). 2023-10-12

[5]
Genome maintenance meets mechanobiology.

Chromosoma. 2024-1

[6]
The Molecular Mechanisms and Therapeutic Prospects of Alternative Lengthening of Telomeres (ALT).

Cancers (Basel). 2023-3-23

[7]
Telomere Fragility and MiDAS: Managing the Gaps at the End of the Road.

Genes (Basel). 2023-1-29

[8]
Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies.

Nat Rev Cancer. 2022-9

[9]
Alternative Lengthening of Telomeres and Mediated Telomere Synthesis.

Cancers (Basel). 2022-4-27

[10]
TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance.

Nat Commun. 2022-4-28

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