Carl P. Lehmann

Centro de Biología Molecular Severo Ochoa

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José Antonio Tercero

Centro de Biología Molecular Severo Ochoa

Irene Saugar

Centro de Biología Molecular Severo Ochoa

Amanda Ernlund

Johns Hopkins University Applied Physics Laboratory

Dana Branzei

IFOM

Kristi L. Neufeld

The University of Kansas Cancer Center

Kaitlyn Carl

University of Kansas

William McGuinness

University of Oxford

Andy Wolfe

University of Kansas

Nicole Baranda Balmaceda

University of Colorado Anschutz Medical Campus

Barnabás Szakál

IFOM

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IFOM

University of Kansas

Centro de Biología Molecular Severo Ochoa

Universidad Autónoma de Madrid

Consejo Superior de Investigaciones Científicas

University of Kansas Medical Center

Cancer Research UK

University of Geneva

The University of Kansas Cancer Center

University Medical Center

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Expression of Concern: Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion. J. Cell Sci. doi: 10.1242/jcs.197574

Journal of Cell Science (2017)

Andy Wolfe Amanda Ernlund William McGuinness Carl P. Lehmann Kaitlyn Carl

This Expression of Concern relates to the article 'Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion' by Andy R. Wolfe, Amanda Ernlund, William McGuinness, Carl Lehmann, Kaitlyn Carl, Nicole Balmaceda and Kristi L. Neufeld (2017). J. Cell Sci. 130, 805-813 (doi: 10.1242/jcs.197574).We have recently been made aware of concerns regarding some of the data in Fig. 2A and B, and Fig. 3A. After discussion with the corresponding author, Kristi Neufeld, this matter has been referred to the authors' institute. Journal of Cell Science is publishing this note to make readers aware of the issue, and we will provide further information once it has been resolved.This course of action follows the advice set out by COPE (Committee on Publication Ethics), of which Journal of Cell Science is a member.

10.1242/jcs.210690

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Mus81-Mms4 endonuclease is an Esc2-STUbL-Cullin8 mitotic substrate impacting on genome integrity

Nature Communications (2020)

Anja Waizenegger Madhusoodanan Urulangodi Carl P. Lehmann Teresa Anne Clarisse Reyes Irene Saugar

Abstract The Mus81-Mms4 nuclease is activated in G2/M via Mms4 phosphorylation to allow resolution of persistent recombination structures. However, the fate of the activated phosphorylated Mms4 remains unknown. Here we find that Mms4 is engaged by (poly)SUMOylation and ubiquitylation and targeted for proteasome degradation, a process linked to the previously described Mms4 phosphorylation cycle. Mms4 is a mitotic substrate for the SUMO-Targeted Ubiquitin ligase Slx5/8, the SUMO-like domain-containing protein Esc2, and the Mms1-Cul8 ubiquitin ligase. In the absence of these activities, phosphorylated Mms4 accumulates on chromatin in an active state in the next G1, subsequently causing abnormal processing of replication-associated recombination intermediates and delaying the activation of the DNA damage checkpoint. Mus81-Mms4 mutants that stabilize phosphorylated Mms4 have similar detrimental effects on genome integrity. Overall, our findings highlight a replication protection function for Esc2-STUbL-Cul8 and emphasize the importance for genome stability of resetting phosphorylated Mms4 from one cycle to another.

Nuclease

10.1038/s41467-020-19503-4

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Citations (25)

Prevention of unwanted recombination at damaged replication forks

Current Genetics (2020)

Carl P. Lehmann Alberto Jiménez-Martín Dana Branzei José Antonio Tercero

Abstract Homologous recombination is essential for the maintenance of genome integrity but must be strictly controlled to avoid dangerous outcomes that produce the opposite effect, genomic instability. During unperturbed chromosome replication, recombination is globally inhibited at ongoing DNA replication forks, which helps to prevent deleterious genomic rearrangements. This inhibition is carried out by Srs2, a helicase that binds to SUMOylated PCNA and has an anti-recombinogenic function at replication forks. However, at damaged stalled forks, Srs2 is counteracted and DNA lesion bypass can be achieved by recombination-mediated template switching. In budding yeast, template switching is dependent on Rad5. In the absence of this protein, replication forks stall in the presence of DNA lesions and cells die. Recently, we showed that in cells lacking Rad5 that are exposed to DNA damage or replicative stress, elimination of the conserved Mgs1/WRNIP1 ATPase allows an alternative mode of DNA damage bypass that is driven by recombination and facilitates completion of chromosome replication and cell viability. We have proposed that Mgs1 is important to prevent a potentially harmful salvage pathway of recombination at damaged stalled forks. In this review, we summarize our current understanding of how unwanted recombination is prevented at damaged stalled replication forks.

Replication protein A

FLP-FRT recombination

DNA re-replication

10.1007/s00294-020-01095-7

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Citations (15)

Suppression of intestinal tumorigenesis in Apc mutant mice by Musashi-1 deletion

Journal of Cell Science (2017)

Andy Wolfe Amanda Ernlund William McGuinness Carl P. Lehmann Kaitlyn Carl

Therapeutic strategies based on a specific oncogenic target are better justified when elimination of that particular oncogene reduces tumorigenesis in a model organism. One such oncogene, Musashi-1 (Msi-1), regulates translation of target mRNAs and is implicated in promoting tumorigenesis in the colon and other tissues. Msi-1 targets include the tumor suppressor adenomatous polyposis coli (Apc), a Wnt pathway antagonist lost in ∼80% of all colorectal cancers. Cell culture experiments have established that Msi-1 is a Wnt target, thus positioning Msi-1 and Apc as mutual antagonists in a mutually repressive feedback loop. Here, we report that intestines from mice lacking Msi-1 display aberrant Apc and Msi-1 mutually repressive feedback, reduced Wnt and Notch signaling, decreased proliferation, and changes in stem cell populations, features predicted to suppress tumorigenesis. Indeed, mice with germline Apc mutations (ApcMin ) or with the Apc1322T truncation mutation have a dramatic reduction in intestinal polyp number when Msi-1 is deleted. Taken together, these results provide genetic evidence that Msi-1 contributes to intestinal tumorigenesis driven by Apc loss, and validate the pursuit of Msi-1 inhibitors as chemo-prevention agents to reduce tumor burden.

Adenomatous polyposis coli

Beta-catenin

10.1242/jcs.197574

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Citations (4)

Spatial regulation of DNA damage tolerance protein Rad5 interconnects genome stability maintenance and proteostasis networks

Nucleic Acids Research (2023)

Carl P. Lehmann Paula González-Fernández José Antonio Tercero

Abstract The Rad5/HLTF protein has a central role in the tolerance to DNA damage by mediating an error-free mode of bypassing unrepaired DNA lesions, and is therefore critical for the maintenance of genome stability. We show in this work that, following cellular stress, Rad5 is regulated by relocalization into two types of nuclear foci that coexist within the same cell, which we termed ‘S’ and ‘I’. Rad5 S-foci form in response to genotoxic stress and are associated with Rad5’s function in maintaining genome stability, whereas I-foci form in the presence of proteotoxic stress and are related to Rad5’s own proteostasis. Rad5 accumulates into S-foci at DNA damage tolerance sites by liquid-liquid phase separation, while I-foci constitute sites of chaperone-mediated sequestration of Rad5 at the intranuclear quality control compartment (INQ). Relocalization of Rad5 into each type of foci involves different pathways and recruitment mechanisms, but in both cases is driven by the evolutionarily conserved E2 ubiquitin-conjugating enzyme Rad6. This coordinated differential relocalization of Rad5 interconnects DNA damage response and proteostasis networks, highlighting the importance of studying these homeostasis mechanisms in tandem. Spatial regulation of Rad5 under cellular stress conditions thus provides a useful biological model to study cellular homeostasis as a whole.

Proteostasis

10.1093/nar/gkad1176

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The Mgs1/WRNIP1 ATPase is required to prevent a recombination salvage pathway at damaged replication forks

Science Advances (2020)

Alberto Jiménez-Martín Irene Saugar Chinnu Rose Joseph Alexandra Mayer Carl P. Lehmann

Mgs1 contributes to genome stability by helping to avoid unwanted recombination at sites of perturbed DNA replication.

Replication

10.1126/sciadv.aaz3327

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Citations (13)

Retraction: Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion. J. Cell Sci. doi: 10.1242/jcs.197574

Journal of Cell Science (2017)

Andy Wolfe Amanda Ernlund William McGuinness Carl P. Lehmann Kaitlyn Carl

The journal is retracting 'Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion' by Andy R. Wolfe, Amanda Ernlund, William McGuinness, Carl Lehmann, Kaitlyn Carl, Nicole Balmaceda and Kristi L. Neufeld (2017). J. Cell Sci. 130, 805-813 (doi: 10.1242/jcs.197574).This notice updates and replaces the Expression of Concern (doi: 10.1242/jcs.210690) relating to the above-referenced article.After concerns were raised by a reader, Journal of Cell Science detected the following issues with the data in the above article: The journal contacted Dr Kristi Neufeld, the corresponding author, who in accordance with institutional policy, referred the issue to the Research Integrity Officer. The journal also contacted the Director of Research Integrity at the University of Kansas.In consultation with the Director of Research Integrity at The University of Kansas, Dr Neufeld then provided the following statement:"This article has been withdrawn by the authors. After notification of inconsistencies in some of the figure panels, the senior author found that Fig. 2A, Fig. 2B and Fig. 3A were not consistent with the primary data. Due to this concern and the length of time required to repeat the experiments in question, the authors wish to retract the paper. We sincerely regret this situation and extend our deepest apologies to the scientific community."The authors have agreed to this retraction.

Statement (logic)

10.1242/jcs.212019

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Fluorescence Microscopy for Analysis of Relocalization of Structure-Specific Endonucleases

Methods in molecular biology (2020)

Carl P. Lehmann Irene Saugar José Antonio Tercero

Budding yeast

10.1007/978-1-0716-0644-5_35

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