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ABSTRACT Cells are under constant attack from genotoxins and rely on a multifaceted DNA damage response (DDR) network to maintain genomic integrity. Central to the DDR are the ATM and ATR

kinases, which respond primarily to double-strand DNA breaks (DSBs) and replication stress, respectively. Optimal ATR signaling requires the RAD9A-RAD1-HUS1 (9-1-1) complex, a toroidal clamp

that is loaded at damage sites and scaffolds signaling and repair factors. Whereas complete ATR pathway inactivation causes embryonic lethality, partial _Hus1_ impairment has been

accomplished in adult mice using hypomorphic (_Hus1__neo_) and null _(Hus1__Δ1_) _Hus1_ alleles, and here we use this system to define the tissue- and cell type-specific actions of the

HUS1-mediated DDR _in vivo_. _Hus1__neo/Δ1_ mice showed hypersensitivity to agents that cause replication stress, including the crosslinking agent mitomycin C (MMC) and the replication

inhibitor hydroxyurea, but not the DSB inducer ionizing radiation. Analysis of tissue morphology, genomic instability, cell proliferation and apoptosis revealed that MMC treatment caused

severe damage in highly replicating tissues of mice with partial _Hus1_ inactivation. The role of the 9-1-1 complex in responding to MMC was partially ATR-independent, as a HUS1 mutant that

was proficient for ATR-induced checkpoint kinase 1 phosphorylation nevertheless conferred MMC hypersensitivity. To assess the interplay between the ATM and ATR pathways in responding to

replication stress _in vivo_, we used _Hus1/Atm_ double mutant mice. Whereas _Hus1__neo/neo_ and _Atm__−/−_ single mutant mice survived low-dose MMC similar to wild-type controls,

_Hus1__neo/neo__Atm__−/−_ double mutants showed striking MMC hypersensitivity, consistent with a model in which MMC exposure in the context of _Hus1_ dysfunction results in DSBs to which the

ATM pathway normally responds. This improved understanding of the inter-dependency between two major DDR mechanisms during the response to a conventional chemotherapeutic illustrates how

inhibition of checkpoint factors such as HUS1 may be effective for the treatment of ATM-deficient and other cancers. Access through your institution Buy or subscribe This is a preview of

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DNA REPLICATION STRESS, DNA REPAIR, AND CANCER Article 06 August 2024 TDP1-INDEPENDENT PATHWAYS IN THE PROCESS AND REPAIR OF TOP1-INDUCED DNA DAMAGE Article Open access 22 July 2022

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Google Scholar  Download references ACKNOWLEDGEMENTS We thank Amy Lyndaker, Steve Jackson and Yaron Galanti for helpful discussions and comments on the manuscript; Natasha Karp for help with

statistical analysis and the staff of the Cornell Lab Animal Services and CARE programs for excellent animal care. This work was supported by a National Institutes of Health grant R01

CA108773 to RSW; a Cornell University College of Veterinary Medicine Graduate Research Assistantship to GB; a Cornell University College of Veterinary Medicine Clinical Fellowship to KRH;

and a National Center for Research Resources grant (S10RR023781) for instrumentation. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Biomedical Sciences, Cornell University,

Ithaca, NY, USA G Balmus, P X Lim, A Oswald, K R Hume, A Cassano, J Pierre, A Hill, T Southard & R S Weiss * Department of Clinical Sciences, Cornell University, Ithaca, NY, USA K R Hume

* Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA W Huang & A August * Department of Population Medicine and Diagnostic Sciences, Cornell University,

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PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Balmus, G., Lim, P., Oswald, A. _et al._ HUS1 regulates _in vivo_ responses to genotoxic chemotherapies. _Oncogene_

35, 662–669 (2016). https://doi.org/10.1038/onc.2015.118 Download citation * Received: 01 July 2014 * Revised: 08 March 2015 * Accepted: 10 March 2015 * Published: 27 April 2015 * Issue

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