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Article: Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities.

Siri, Sebastián Omar / Martino, Julieta / Gottifredi, Vanesa

2021 Volume 13, Issue 12

Abstract: Chromosomal instability (CIN) refers to an increased rate of acquisition of numerical and structural changes in chromosomes and is considered an enabling characteristic of tumors. Given its role as a facilitator of genomic changes, CIN is increasingly ... ...

Abstract	Chromosomal instability (CIN) refers to an increased rate of acquisition of numerical and structural changes in chromosomes and is considered an enabling characteristic of tumors. Given its role as a facilitator of genomic changes, CIN is increasingly being considered as a possible therapeutic target, raising the question of which variables may convert CIN into an ally instead of an enemy during cancer treatment. This review discusses the origins of structural chromosome abnormalities and the cellular mechanisms that prevent and resolve them, as well as how different CIN phenotypes relate to each other. We discuss the possible fates of cells containing structural CIN, focusing on how a few cell duplication cycles suffice to induce profound CIN-mediated genome alterations. Because such alterations can promote tumor adaptation to treatment, we discuss currently proposed strategies to either avoid CIN or enhance CIN to a level that is no longer compatible with cell survival.
Language	English
Publishing date	2021-06-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13123056
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Article: The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA.

Hengel, Sarah R / Oppenheimer, Katherine / Smith, Chelsea / Schaich, Matthew A / Rein, Hayley L / Martino, Julieta / Darrah, Kristie / Ezekwenna, Oluchi / Burton, Kyle / Van Houten, Bennett / Spies, Maria / Bernstein, Kara A

bioRxiv : the preprint server for biology

2024

Abstract: Templated DNA repair that occurs during homologous recombination and replication stress relies on RAD51. RAD51 activity is positively regulated by BRCA2 and the RAD51 paralogs. The Shu complex is a RAD51 paralog-containing complex consisting of SWSAP1 ... ...

Abstract	Templated DNA repair that occurs during homologous recombination and replication stress relies on RAD51. RAD51 activity is positively regulated by BRCA2 and the RAD51 paralogs. The Shu complex is a RAD51 paralog-containing complex consisting of SWSAP1 and SWS1. We demonstrate that SWSAP1-SWS1 binds RAD51, maintains RAD51 filament stability, and enables strand exchange. Using single molecule confocal fluorescence microscopy combined with optical tweezers, we show that SWSAP1-SWS1 decorates RAD51 filaments proficient for homologous recombination. We also find SWSAP1-SWS1 enhances RPA diffusion on ssDNA. Importantly, we show human
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.14.580393
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Article ; Online: The Shu complex is a conserved regulator of homologous recombination.

Martino, Julieta / Bernstein, Kara A

FEMS yeast research

2016 Volume 16, Issue 6

Abstract: Homologous recombination (HR) is an error-free DNA repair mechanism that maintains genome integrity by repairing double-strand breaks (DSBs). Defects in HR lead to genomic instability and are associated with cancer predisposition. A key step in HR is the ...

Abstract	Homologous recombination (HR) is an error-free DNA repair mechanism that maintains genome integrity by repairing double-strand breaks (DSBs). Defects in HR lead to genomic instability and are associated with cancer predisposition. A key step in HR is the formation of Rad51 nucleoprotein filaments which are responsible for the homology search and strand invasion steps that define HR. Recently, the budding yeast Shu complex has emerged as an important regulator of Rad51 along with the other Rad51 mediators including Rad52 and the Rad51 paralogs, Rad55-Rad57. The Shu complex is a heterotetramer consisting of two novel Rad51 paralogs, Psy3 and Csm2, along with Shu1 and a SWIM domain-containing protein, Shu2. Studies done primarily in yeast have provided evidence that the Shu complex regulates HR at several types of DNA DSBs (i.e. replication-associated and meiotic DSBs) and that its role in HR is highly conserved across eukaryotic lineages. This review highlights the main findings of these studies and discusses the proposed specific roles of the Shu complex in many aspects of recombination-mediated DNA repair.
Language	English
Publishing date	2016-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2036775-2
ISSN	1567-1364 ; 1567-1356
ISSN (online)	1567-1364
ISSN	1567-1356
DOI	10.1093/femsyr/fow073
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Article ; Online: Correction: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells.

Martino, Julieta / Siri, Sebastián Omar / Calzetta, Nicolás Luis / Paviolo, Natalia Soledad / Garro, Cintia / Pansa, Maria F / Carbajosa, Sofía / Brown, Aaron C / Bocco, José Luis / Gloger, Israel / Drewes, Gerard / Madauss, Kevin P / Soria, Gastón / Gottifredi, Vanesa

eLife

2023 Volume 12

Language	English
Publishing date	2023-11-14
Publishing country	England
Document type	Published Erratum
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.94414
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Article ; Online: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells.

eLife

2023 Volume 12

Abstract: The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2- ... ...

Abstract	The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2-deficient cells. In contrast, here we show that inhibiting ROCK in BRCA2-deficient cells triggers SL independently from acute replication stress. Such SL is preceded by polyploidy and binucleation resulting from cytokinesis failure. Such initial mitosis abnormalities are followed by other M phase defects, including anaphase bridges and abnormal mitotic figures associated with multipolar spindles, supernumerary centrosomes and multinucleation. SL was also triggered by inhibiting Citron Rho-interacting kinase, another enzyme that, similarly to ROCK, regulates cytokinesis. Together, these observations demonstrate that cytokinesis failure triggers mitotic abnormalities and SL in BRCA2-deficient cells. Furthermore, the prevention of mitotic entry by depletion of Early mitotic inhibitor 1 (EMI1) augmented the survival of BRCA2-deficient cells treated with ROCK inhibitors, thus reinforcing the association between M phase and cell death in BRCA2-deficient cells. This novel SL differs from the one triggered by PARPi and uncovers mitosis as an Achilles heel of BRCA2-deficient cells.
MeSH term(s)	Anaphase ; DNA Damage ; Mitosis ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Synthetic Lethal Mutations ; rho-Associated Kinases/antagonists & inhibitors ; BRCA2 Protein/genetics ; Humans
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; rho-Associated Kinases (EC 2.7.11.1) ; BRCA2 Protein
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.80254
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Article ; Online: Correction: Unscheduled MRE11 activity triggers cell death but not chromosome instability in polymerase eta-depleted cells subjected to UV irradiation.

Federico, María Belén / Siri, Sebastián Omar / Calzetta, Nicolás Luis / Paviolo, Natalia Soledad / de la Vega, María Belén / Martino, Julieta / Campana, María Carolina / Wiesmüller, Lisa / Gottifredi, Vanesa

Oncogene

2023 Volume 42, Issue 48, Page(s) 3589

Language	English
Publishing date	2023-09-27
Publishing country	England
Document type	Published Erratum
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-023-02854-9
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Article ; Online: Hexavalent Chromium Targets Securin to Drive Numerical Chromosome Instability in Human Lung Cells.

Toyoda, Jennifer H / Martino, Julieta / Speer, Rachel M / Meaza, Idoia / Lu, Haiyan / Williams, Aggie R / Bolt, Alicia M / Kouokam, Joseph Calvin / Aboueissa, Abou El-Makarim / Wise, John Pierce

International journal of molecular sciences

2023 Volume 25, Issue 1

Abstract: Hexavalent chromium [Cr(VI)] is a known human lung carcinogen with widespread exposure in environmental and occupational settings. Despite well-known cancer risks, the molecular mechanisms of Cr(VI)-induced carcinogenesis are not well understood, but a ... ...

Abstract	Hexavalent chromium [Cr(VI)] is a known human lung carcinogen with widespread exposure in environmental and occupational settings. Despite well-known cancer risks, the molecular mechanisms of Cr(VI)-induced carcinogenesis are not well understood, but a major driver of Cr(VI) carcinogenesis is chromosome instability. Previously, we reported Cr(VI) induced numerical chromosome instability, premature centriole disengagement, centrosome amplification, premature centromere division, and spindle assembly checkpoint bypass. A key regulator of these events is securin, which acts by regulating the cleavage ability of separase. Thus, in this study we investigated securin disruption by Cr(VI) exposure. We exposed human lung cells to a particulate Cr(VI) compound, zinc chromate, for acute (24 h) and prolonged (120 h) time points. We found prolonged Cr(VI) exposure caused marked decrease in securin levels and function. After prolonged exposure at the highest concentration, securin protein levels were decreased to 15.3% of control cells, while securin mRNA quantification was 7.9% relative to control cells. Additionally, loss of securin function led to increased separase activity manifested as enhanced cleavage of separase substrates; separase, kendrin, and SCC1. These data show securin is targeted by prolonged Cr(VI) exposure in human lung cells. Thus, a new mechanistic model for Cr(VI)-induced carcinogenesis emerges with centrosome and centromere disruption as key components of numerical chromosome instability, a key driver in Cr(VI) carcinogenesis.
MeSH term(s)	Humans ; Securin/genetics ; Separase ; Carcinogenesis ; Chromosomal Instability ; Chromium
Chemical Substances	chromium hexavalent ion (18540-29-9) ; Securin ; Separase (EC 3.4.22.49) ; Chromium (0R0008Q3JB)
Language	English
Publishing date	2023-12-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25010256
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Article ; Online: Hexavalent Chromium-Induced Chromosome Instability Drives Permanent and Heritable Numerical and Structural Changes and a DNA Repair-Deficient Phenotype.

Wise, Sandra S / Aboueissa, Abou El-Makarim / Martino, Julieta / Wise, John Pierce

Cancer research

2018 Volume 78, Issue 15, Page(s) 4203–4214

Abstract: A key hypothesis for how hexavalent chromium [Cr(VI)] causes cancer is that it drives chromosome instability (CIN), which leads to neoplastic transformation. Studies show chronic Cr(VI) can affect DNA repair and induce centrosome amplification, which can ...

Abstract	A key hypothesis for how hexavalent chromium [Cr(VI)] causes cancer is that it drives chromosome instability (CIN), which leads to neoplastic transformation. Studies show chronic Cr(VI) can affect DNA repair and induce centrosome amplification, which can lead to structural and numerical CIN. However, no studies have considered whether these outcomes are transient or permanent. In this study, we exposed human lung cells to particulate Cr(VI) for three sequential 24-hour periods, each separated by about a month. After each treatment, cells were seeded at colony-forming density, cloned, expanded, and retreated, creating three generations of clonal cell lines. Each generation of clones was tested for chromium sensitivity, chromosome complement, DNA repair capacity, centrosome amplification, and the ability to grow in soft agar. After the first treatment, Cr(VI)-treated clones exhibited a normal chromosome complement, but some clones showed a repair-deficient phenotype and amplified centrosomes. After the second exposure, more than half of the treated clones acquired an abnormal karyotype including numerical and structural alterations, with many exhibiting deficient DNA double-strand break repair and amplified centrosomes. The third treatment produced new abnormal clones, with previously abnormal clones acquiring additional abnormalities and most clones exhibiting repair deficiency. CIN, repair deficiency, and amplified centrosomes were all permanent and heritable phenotypes of repeated Cr(VI) exposure. These outcomes support the hypothesis that CIN is a key mechanism of Cr(VI)-induced carcinogenesis.
MeSH term(s)	Carcinogenesis/drug effects ; Carcinogens/pharmacology ; Cell Line ; Cell Transformation, Neoplastic/drug effects ; Centrosome/drug effects ; Chromium/pharmacology ; Chromosomal Instability/drug effects ; DNA Breaks, Double-Stranded/drug effects ; DNA Damage/drug effects ; DNA Repair/drug effects ; DNA Repair-Deficiency Disorders/drug therapy ; Humans ; Lung/drug effects ; Phenotype
Chemical Substances	Carcinogens ; Chromium (0R0008Q3JB) ; chromium hexavalent ion (18540-29-9)
Language	English
Publishing date	2018-06-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-18-0531
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Article ; Online: Unscheduled MRE11 activity triggers cell death but not chromosome instability in polymerase eta-depleted cells subjected to UV irradiation.

Oncogene

2020 Volume 39, Issue 19, Page(s) 3952–3964

Abstract: The elimination of DNA polymerase eta (pol η) causes discontinuous DNA elongation and fork stalling in UV-irradiated cells. Such alterations in DNA replication are followed by S-phase arrest, DNA double-strand break (DSB) accumulation, and cell death. ... ...

Abstract	The elimination of DNA polymerase eta (pol η) causes discontinuous DNA elongation and fork stalling in UV-irradiated cells. Such alterations in DNA replication are followed by S-phase arrest, DNA double-strand break (DSB) accumulation, and cell death. However, their molecular triggers and the relative timing of these events have not been fully elucidated. Here, we report that DSBs accumulate relatively early after UV irradiation in pol η-depleted cells. Despite the availability of repair pathways, DSBs persist and chromosome instability (CIN) is not detectable. Later on cells with pan-nuclear γH2AX and massive exposure of template single-stranded DNA (ssDNA), which indicate severe replication stress, accumulate and such events are followed by cell death. Reinforcing the causal link between the accumulation of pan-nuclear ssDNA/γH2AX signals and cell death, downregulation of RPA increased both replication stress and the cell death of pol η-deficient cells. Remarkably, DSBs, pan-nuclear ssDNA/γH2AX, S-phase arrest, and cell death are all attenuated by MRE11 nuclease knockdown. Such results suggest that unscheduled MRE11-dependent activities at replicating DNA selectively trigger cell death, but not CIN. Together these results show that pol η-depletion promotes a type of cell death that may be attractive as a therapeutic tool because of the lack of CIN.
MeSH term(s)	Cell Cycle Checkpoints/radiation effects ; Cell Death/genetics ; Chromosomal Instability/radiation effects ; DNA Breaks, Double-Stranded/radiation effects ; DNA Damage/radiation effects ; DNA Repair/radiation effects ; DNA Replication/radiation effects ; DNA, Single-Stranded/radiation effects ; DNA-Directed DNA Polymerase/genetics ; Histones/genetics ; Humans ; MRE11 Homologue Protein/genetics ; S Phase/radiation effects ; Ultraviolet Rays/adverse effects
Chemical Substances	DNA, Single-Stranded ; H2AX protein, human ; Histones ; DNA-Directed DNA Polymerase (EC 2.7.7.7) ; Rad30 protein (EC 2.7.7.7) ; MRE11 Homologue Protein (EC 3.1.-)
Language	English
Publishing date	2020-03-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-020-1265-9
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Article ; Online: Chronic Exposure to Particulate Chromate Induces Premature Centrosome Separation and Centriole Disengagement in Human Lung Cells.

Martino, Julieta / Holmes, Amie L / Xie, Hong / Wise, Sandra S / Wise, John Pierce

Toxicological sciences : an official journal of the Society of Toxicology

2015 Volume 147, Issue 2, Page(s) 490–499

Abstract: Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen. Lung tumors are characterized by structural and numerical chromosome instability. Centrosome amplification is a phenotype commonly found in solid tumors, including lung ...

Abstract	Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen. Lung tumors are characterized by structural and numerical chromosome instability. Centrosome amplification is a phenotype commonly found in solid tumors, including lung tumors, which strongly correlates with chromosome instability. Human lung cells exposed to Cr(VI) exhibit centrosome amplification but the underlying phenotypes and mechanisms remain unknown. In this study, we further characterize the phenotypes of Cr(VI)-induced centrosome abnormalities. We show that Cr(VI)-induced centrosome amplification correlates with numerical chromosome instability. We also show chronic exposure to particulate Cr(VI) induces centrosomes with supernumerary centrioles and acentriolar centrosomes in human lung cells. Moreover, chronic exposure to particulate Cr(VI) affects the timing of important centriolar events. Specifically, chronic exposure to particulate Cr(VI) causes premature centriole disengagement in S and G2 phase cells. It also induces premature centrosome separation in interphase. Altogether, our data suggest that chronic exposure to particulate Cr(VI) targets the protein linkers that hold centrioles together. These centriolar linkers are important for key events of the centrosome cycle and their premature disruption might underlie Cr(VI)-induced centrosome amplification.
MeSH term(s)	Cell Line ; Centrioles/drug effects ; Centrosome/drug effects ; Chromates/administration & dosage ; Chromates/toxicity ; Chromium/administration & dosage ; Chromium/toxicity ; Chromosomal Instability/drug effects ; Humans ; Lung/cytology ; Lung/drug effects ; Particulate Matter/administration & dosage ; Particulate Matter/toxicity ; Zinc Compounds/administration & dosage ; Zinc Compounds/toxicity
Chemical Substances	Chromates ; Particulate Matter ; Zinc Compounds ; zinc chromate (05F2837HUF) ; Chromium (0R0008Q3JB) ; chromium hexavalent ion (18540-29-9)
Language	English
Publishing date	2015-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfv146
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