SLX4IP Antagonizes Promiscuous BLM Activity During ALT Maintenance

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Aug 27

PMID 31447390

Citations 46

Authors

Stephanie Panier

Marija Maric

Graeme Hewitt

Emily Mason-Osann

Himabindu Gali

Anqi Dai

Adam Labadorf

Jean-Hugues Guervilly

Philip Ruis

Sandra Segura-Bayona

Ondrej Belan

Paulina Marzec

Pierre-Henri L Gaillard

Rachel L Flynn

Simon J Boulton

Affiliations

Soon will be listed here.

Abstract

Cancer cells acquire unlimited proliferative capacity by either re-expressing telomerase or inducing alternative lengthening of telomeres (ALT), which relies on telomere recombination. Here, we show that ALT recombination requires coordinate regulation of the SMX and BTR complexes to ensure the appropriate balance of resolution and dissolution activities at recombining telomeres. Critical to this control is SLX4IP, which accumulates at ALT telomeres and interacts with SLX4, XPF, and BLM. Loss of SLX4IP increases ALT-related phenotypes, which is incompatible with cell growth following concomitant loss of SLX4. Inactivation of BLM is sufficient to rescue telomere aggregation and the synthetic growth defect in this context, suggesting that SLX4IP favors SMX-dependent resolution by antagonizing promiscuous BLM activity during ALT recombination. Finally, we show that SLX4IP is inactivated in a subset of ALT-positive osteosarcomas. Collectively, our findings uncover an SLX4IP-dependent regulatory mechanism critical for telomere maintenance in ALT cancer cells.

Citing Articles

Multiple functions of the ALT favorite helicase, BLM.

Chang S, Tan J, Bao R, Zhang Y, Tong J, Jia T Cell Biosci. 2025; 15(1):31.

PMID: 40025590 PMC: 11871798. DOI: 10.1186/s13578-025-01372-3.

Strategic base modifications refine RNA function and reduce CRISPR-Cas9 off-targets.

Zhang K, Shen W, Zhao Y, Xu X, Liu X, Qi Q Nucleic Acids Res. 2025; 53(4).

PMID: 39964477 PMC: 11833691. DOI: 10.1093/nar/gkaf082.

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

Dubois J, Bonnell E, Filion A, Frion J, Zimmer S, Khan M Proc Natl Acad Sci U S A. 2025; 122(2):e2419712122.

PMID: 39772744 PMC: 11745411. DOI: 10.1073/pnas.2419712122.

TGF-β superfamily-induced transcriptional activation pathways establish the RAD52-dependent ALT machinery during malignant transformation of MPNSTs.

Choi E, Lee J, Kim H, Kim Y, Kim S Sci Rep. 2024; 14(1):26475.

PMID: 39488637 PMC: 11531527. DOI: 10.1038/s41598-024-76732-z.

SUMO promotes DNA repair protein collaboration to support alternative telomere lengthening in the absence of PML.

Zhao R, Xu M, Yu X, Wondisford A, Lackner R, Salsman J Genes Dev. 2024; 38(13-14):614-630.

PMID: 39038850 PMC: 11368244. DOI: 10.1101/gad.351667.124.

References

Henson J, Lau L, Koch S, Martin La Rotta N, Dagg R, Reddel R . The C-Circle Assay for alternative-lengthening-of-telomeres activity. Methods. 2016; 114:74-84. DOI: 10.1016/j.ymeth.2016.08.016. View

Nabetani A, Ishikawa F . Unusual telomeric DNAs in human telomerase-negative immortalized cells. Mol Cell Biol. 2008; 29(3):703-13. PMC: 2630689. DOI: 10.1128/MCB.00603-08. View

Dilley R, Verma P, Cho N, Winters H, Wondisford A, Greenberg R . Break-induced telomere synthesis underlies alternative telomere maintenance. Nature. 2016; 539(7627):54-58. PMC: 5384111. DOI: 10.1038/nature20099. View

Houghton P, Morton C, Tucker C, Payne D, Favours E, Cole C . The pediatric preclinical testing program: description of models and early testing results. Pediatr Blood Cancer. 2006; 49(7):928-40. DOI: 10.1002/pbc.21078. View

Navratil M, Terman A, Arriaga E . Giant mitochondria do not fuse and exchange their contents with normal mitochondria. Exp Cell Res. 2007; 314(1):164-72. DOI: 10.1016/j.yexcr.2007.09.013. View

Wu Y, Mitchell T, Zhu X . Human XPF controls TRF2 and telomere length maintenance through distinctive mechanisms. Mech Ageing Dev. 2008; 129(10):602-10. DOI: 10.1016/j.mad.2008.08.004. View

Stavropoulos D, Bradshaw P, Li X, Pasic I, Truong K, Ikura M . The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Hum Mol Genet. 2002; 11(25):3135-44. DOI: 10.1093/hmg/11.25.3135. View

Cesare A, Griffith J . Telomeric DNA in ALT cells is characterized by free telomeric circles and heterogeneous t-loops. Mol Cell Biol. 2004; 24(22):9948-57. PMC: 525488. DOI: 10.1128/MCB.24.22.9948-9957.2004. View

Raynard S, Bussen W, Sung P . A double Holliday junction dissolvasome comprising BLM, topoisomerase IIIalpha, and BLAP75. J Biol Chem. 2006; 281(20):13861-4. DOI: 10.1074/jbc.C600051200. View

10.

Lundblad V, Blackburn E . An alternative pathway for yeast telomere maintenance rescues est1- senescence. Cell. 1993; 73(2):347-60. DOI: 10.1016/0092-8674(93)90234-h. View

11.

Xu D, Guo R, Sobeck A, Bachrati C, Yang J, Enomoto T . RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability. Genes Dev. 2008; 22(20):2843-55. PMC: 2569887. DOI: 10.1101/gad.1708608. View

12.

Munoz P, Blanco R, Flores J, Blasco M . XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Nat Genet. 2005; 37(10):1063-71. DOI: 10.1038/ng1633. View

13.

Biebricher A, Hirano S, Enzlin J, Wiechens N, Streicher W, Huttner D . PICH: a DNA translocase specially adapted for processing anaphase bridge DNA. Mol Cell. 2013; 51(5):691-701. PMC: 4161920. DOI: 10.1016/j.molcel.2013.07.016. View

14.

Makarov V, Hirose Y, Langmore J . Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell. 1997; 88(5):657-66. DOI: 10.1016/s0092-8674(00)81908-x. View

15.

Baumann C, Korner R, Hofmann K, Nigg E . PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell. 2007; 128(1):101-14. DOI: 10.1016/j.cell.2006.11.041. View

16.

Wan B, Yin J, Horvath K, Sarkar J, Chen Y, Wu J . SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Cell Rep. 2013; 4(5):861-9. PMC: 4334113. DOI: 10.1016/j.celrep.2013.08.017. View

17.

Mason-Osann E, Dai A, Floro J, Lock Y, Reiss M, Gali H . Identification of a novel gene fusion in ALT positive osteosarcoma. Oncotarget. 2018; 9(67):32868-32880. PMC: 6132345. DOI: 10.18632/oncotarget.26029. View

18.

Zeng S, Xiang T, Pandita T, Gonzalez-Suarez I, Gonzalo S, Harris C . Telomere recombination requires the MUS81 endonuclease. Nat Cell Biol. 2009; 11(5):616-23. PMC: 2675667. DOI: 10.1038/ncb1867. View

19.

Diplas B, He X, Brosnan-Cashman J, Liu H, Chen L, Wang Z . The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma. Nat Commun. 2018; 9(1):2087. PMC: 5970234. DOI: 10.1038/s41467-018-04448-6. View

20.

Liu X, Kim C, Yang J, Jemmerson R, Wang X . Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996; 86(1):147-57. DOI: 10.1016/s0092-8674(00)80085-9. View