Micronuclear collapse from oxidative damage-Reference-Cited by-同舟云学术

Micronuclear collapse from oxidative damage

Published:2024-08-30 Issue:6712 Volume:385 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Di Bona Melody¹²^ORCID,Chen Yanyang³^ORCID,Agustinus Albert S.¹²⁴^ORCID,Mazzagatti Alice⁵^ORCID,Duran Mercedes A.¹²^ORCID,Deyell Matthew⁶^ORCID,Bronder Daniel¹²^ORCID,Hickling James³^ORCID,Hong Christy¹²^ORCID,Scipioni Lorenzo⁷⁸^ORCID,Tedeschi Giulia⁷⁸^ORCID,Martin Sara⁹^ORCID,Li Jun¹²^ORCID,Ruzgaitė Aušrinė¹²,Riaz Nadeem¹^ORCID,Shah Parin¹⁰,D’Souza Edridge K.¹⁰^ORCID,Brodtman D. Zack¹⁰^ORCID,Sidoli Simone¹¹^ORCID,Diplas Bill¹,Jalan Manisha¹^ORCID,Lee Nancy Y.¹,Ordureau Alban¹²^ORCID,Izar Benjamin¹⁰^ORCID,Laughney Ashley M.⁶^ORCID,Powell Simon¹^ORCID,Gratton Enrico⁷^ORCID,Santaguida Stefano⁹¹³^ORCID,Maciejowski John³,Ly Peter⁵^ORCID,Jeitner Thomas M.¹⁴^ORCID,Bakhoum Samuel F.¹²^ORCID

Affiliation:

1. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

2. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

3. Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

4. Pharmacology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA.

5. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

6. Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10065, USA.

7. School of Engineering, University of California, Irvine, CA 92697, USA.

8. Laboratory for Fluorescence Dynamics, University of California, Irvine, Irvine, CA 92617, USA.

9. Department of Experimental Oncology, European Institute of Oncology IRCCS, 20141 Milan, Italy.

10. Systems Biology Department, Columbia University, New York, NY 10032, USA.

11. Department of Biochemistry, Albert Einstein College of Medicine, New York, NY 10461, USA.

12. Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

13. Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy.

14. Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA.

Abstract

Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adj8691

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