Loss of SLX4IP leads to common fragile site instability and compromises DNA interstrand crosslink repair in vivo

Andreas Ingham; Mukundhan Ramaswami; Ramanagouda Ramangoudr-Bhojappa; David Pladevall-Morera; Flavia De Santis; Javier Terriente; Ivan M. Muñoz; John Rouse; Settara C. Chandrasekharappa; Andres J. Lopez-Contreras

doi:10.1016/j.jbc.2025.110244

Loss of SLX4IP leads to common fragile site instability and compromises DNA interstrand crosslink repair in vivo

Andreas Ingham, Mukundhan Ramaswami, Ramanagouda Ramangoudr-Bhojappa, David Pladevall-Morera, Flavia De Santis, Javier Terriente, Ivan M. Muñoz, John Rouse, Settara C. Chandrasekharappa, Andres J. Lopez-Contreras (Lead / Corresponding author)

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Abstract

Common fragile sites (CFSs) are chromosomal loci with inherent characteristics that make them difficult to fully replicate thus rendering them vulnerable to replication stress (RS). Under-replicated CFSs manifest as cytogenetic gaps and breaks on metaphase chromosomes. Moreover, CFSs are hotspots for tumorigenic chromosomal rearrangements. The Fanconi anemia (FA) pathway is at the core of a network of proteins that work to safeguard CFSs during replication and RS. Here, we uncover a novel role of SLX4IP in maintaining CFS stability. We show that SLX4IP localizes stressed CFSs and that its loss exacerbates genome instability, including CFS expression. Furthermore, direct SLX4IP depletion leads to impaired replication and growth deficiencies. SLX4IP and FANCP/SLX4 are epistatic, suggesting that SLX4IP acts with SLX4 to maintain CFS stability. Finally, zebrafish larvae with homozygous knockout of the slx4ip gene showed higher frequency of embryonic anomalies and sensitivity to DNA crosslinking agents, a typical cellular characteristic of patients with FA. Our results establish a causal link between SLX4IP deficiency and chromosomal instability, which may explain how SLX4IP dysregulation contributes to cancer development.

Original language	English
Article number	110244
Journal	Journal of Biological Chemistry
Volume	301
Issue number	6
Early online date	16 May 2025
DOIs	https://doi.org/10.1016/j.jbc.2025.110244
Publication status	Published - 20 Jun 2025

Keywords

common fragile sites
Fanconi anemia
interstrand crosslink repair
SLX4
SLX4IP
zebrafish

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jbc.2025.110244Licence: CC BY-NC-ND

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Ingham, A., Ramaswami, M., Ramangoudr-Bhojappa, R., Pladevall-Morera, D., De Santis, F., Terriente, J., Muñoz, I. M., Rouse, J., Chandrasekharappa, S. C., & Lopez-Contreras, A. J. (2025). Loss of SLX4IP leads to common fragile site instability and compromises DNA interstrand crosslink repair in vivo. Journal of Biological Chemistry, 301(6), Article 110244. https://doi.org/10.1016/j.jbc.2025.110244

@article{6e9fc3fb3ac246ea878dd169d03d7d77,

title = "Loss of SLX4IP leads to common fragile site instability and compromises DNA interstrand crosslink repair in vivo",

abstract = "Common fragile sites (CFSs) are chromosomal loci with inherent characteristics that make them difficult to fully replicate thus rendering them vulnerable to replication stress (RS). Under-replicated CFSs manifest as cytogenetic gaps and breaks on metaphase chromosomes. Moreover, CFSs are hotspots for tumorigenic chromosomal rearrangements. The Fanconi anemia (FA) pathway is at the core of a network of proteins that work to safeguard CFSs during replication and RS. Here, we uncover a novel role of SLX4IP in maintaining CFS stability. We show that SLX4IP localizes stressed CFSs and that its loss exacerbates genome instability, including CFS expression. Furthermore, direct SLX4IP depletion leads to impaired replication and growth deficiencies. SLX4IP and FANCP/SLX4 are epistatic, suggesting that SLX4IP acts with SLX4 to maintain CFS stability. Finally, zebrafish larvae with homozygous knockout of the slx4ip gene showed higher frequency of embryonic anomalies and sensitivity to DNA crosslinking agents, a typical cellular characteristic of patients with FA. Our results establish a causal link between SLX4IP deficiency and chromosomal instability, which may explain how SLX4IP dysregulation contributes to cancer development.",

keywords = "common fragile sites, Fanconi anemia, interstrand crosslink repair, SLX4, SLX4IP, zebrafish",

author = "Andreas Ingham and Mukundhan Ramaswami and Ramanagouda Ramangoudr-Bhojappa and David Pladevall-Morera and \{De Santis\}, Flavia and Javier Terriente and Mu{\~n}oz, \{Ivan M.\} and John Rouse and Chandrasekharappa, \{Settara C.\} and Lopez-Contreras, \{Andres J.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = jun,

day = "20",

doi = "10.1016/j.jbc.2025.110244",

language = "English",

volume = "301",

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Ingham, A, Ramaswami, M, Ramangoudr-Bhojappa, R, Pladevall-Morera, D, De Santis, F, Terriente, J, Muñoz, IM , Rouse, J, Chandrasekharappa, SC & Lopez-Contreras, AJ 2025, 'Loss of SLX4IP leads to common fragile site instability and compromises DNA interstrand crosslink repair in vivo', Journal of Biological Chemistry, vol. 301, no. 6, 110244. https://doi.org/10.1016/j.jbc.2025.110244

TY - JOUR

T1 - Loss of SLX4IP leads to common fragile site instability and compromises DNA interstrand crosslink repair in vivo

AU - Ingham, Andreas

AU - Ramaswami, Mukundhan

AU - Ramangoudr-Bhojappa, Ramanagouda

AU - Pladevall-Morera, David

AU - De Santis, Flavia

AU - Terriente, Javier

AU - Muñoz, Ivan M.

AU - Rouse, John

AU - Chandrasekharappa, Settara C.

AU - Lopez-Contreras, Andres J.

PY - 2025/6/20

Y1 - 2025/6/20

N2 - Common fragile sites (CFSs) are chromosomal loci with inherent characteristics that make them difficult to fully replicate thus rendering them vulnerable to replication stress (RS). Under-replicated CFSs manifest as cytogenetic gaps and breaks on metaphase chromosomes. Moreover, CFSs are hotspots for tumorigenic chromosomal rearrangements. The Fanconi anemia (FA) pathway is at the core of a network of proteins that work to safeguard CFSs during replication and RS. Here, we uncover a novel role of SLX4IP in maintaining CFS stability. We show that SLX4IP localizes stressed CFSs and that its loss exacerbates genome instability, including CFS expression. Furthermore, direct SLX4IP depletion leads to impaired replication and growth deficiencies. SLX4IP and FANCP/SLX4 are epistatic, suggesting that SLX4IP acts with SLX4 to maintain CFS stability. Finally, zebrafish larvae with homozygous knockout of the slx4ip gene showed higher frequency of embryonic anomalies and sensitivity to DNA crosslinking agents, a typical cellular characteristic of patients with FA. Our results establish a causal link between SLX4IP deficiency and chromosomal instability, which may explain how SLX4IP dysregulation contributes to cancer development.

AB - Common fragile sites (CFSs) are chromosomal loci with inherent characteristics that make them difficult to fully replicate thus rendering them vulnerable to replication stress (RS). Under-replicated CFSs manifest as cytogenetic gaps and breaks on metaphase chromosomes. Moreover, CFSs are hotspots for tumorigenic chromosomal rearrangements. The Fanconi anemia (FA) pathway is at the core of a network of proteins that work to safeguard CFSs during replication and RS. Here, we uncover a novel role of SLX4IP in maintaining CFS stability. We show that SLX4IP localizes stressed CFSs and that its loss exacerbates genome instability, including CFS expression. Furthermore, direct SLX4IP depletion leads to impaired replication and growth deficiencies. SLX4IP and FANCP/SLX4 are epistatic, suggesting that SLX4IP acts with SLX4 to maintain CFS stability. Finally, zebrafish larvae with homozygous knockout of the slx4ip gene showed higher frequency of embryonic anomalies and sensitivity to DNA crosslinking agents, a typical cellular characteristic of patients with FA. Our results establish a causal link between SLX4IP deficiency and chromosomal instability, which may explain how SLX4IP dysregulation contributes to cancer development.

KW - common fragile sites

KW - Fanconi anemia

KW - interstrand crosslink repair

KW - SLX4

KW - SLX4IP

KW - zebrafish

UR - https://www.scopus.com/pages/publications/105008445874

U2 - 10.1016/j.jbc.2025.110244

DO - 10.1016/j.jbc.2025.110244

M3 - Article

C2 - 40383148

AN - SCOPUS:105008445874

SN - 0021-9258

VL - 301

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 6

M1 - 110244

ER -

Loss of SLX4IP leads to common fragile site instability and compromises DNA interstrand crosslink repair in vivo

Abstract

Keywords

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UN SDGs

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