UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

Ron D. Jachimowicz; Filippo Beleggia; Jörg Isensee; Bhagya Bhavana Velpula; Jonas Goergens; Matias A. Bustos; Markus A. Doll; Anjana Shenoy; Cintia Checa-Rodriguez; Janica Lea Wiederstein; Keren Baranes-Bachar; Christoph Bartenhagen; Falk Hertwig; Nizan Teper; Tomohiko Nishi; Anna Schmitt; Felix Distelmaier; Hermann Josef Lüdecke; Beate Albrecht; Marcus Krüger; Björn Schumacher; Tamar Geiger; Dave S.B. Hoon; Pablo Huertas; Matthias Fischer; Tim Hucho; Martin Peifer; Yael Ziv; H. Christian Reinhardt; Dagmar Wieczorek; Yosef Shiloh

doi:10.1016/j.cell.2018.11.024

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

Ron D. Jachimowicz^*, Filippo Beleggia, Jörg Isensee, Bhagya Bhavana Velpula, Jonas Goergens, Matias A. Bustos, Markus A. Doll, Anjana Shenoy, Cintia Checa-Rodriguez, Janica Lea Wiederstein, Keren Baranes-Bachar, Christoph Bartenhagen, Falk Hertwig, Nizan Teper, Tomohiko Nishi, Anna Schmitt, Felix Distelmaier, Hermann Josef Lüdecke, Beate Albrecht, Marcus KrügerBjörn Schumacher, Tamar Geiger, Dave S.B. Hoon, Pablo Huertas, Matthias Fischer, Tim Hucho, Martin Peifer, Yael Ziv, H. Christian Reinhardt, Dagmar Wieczorek, Yosef Shiloh

^*Corresponding author for this work

Human Molecular Genetics Biochemistry

Research output: Contribution to journal › Article › peer-review

87 Scopus citations

Abstract

Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.

Original language	English
Pages (from-to)	505-519.e22
Journal	Cell
Volume	176
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2018.11.024
State	Published - 24 Jan 2019

Funding

Funders	Funder number
ISF-NSFC
Israel Cancer Research Fund
AstraZeneca
Merck
Gilead Sciences
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
AbbVie
Deutsche Forschungsgemeinschaft	KFO-286-RP2, KFO-286-CP2, DI1731/2-1, JA2439/1-1
German-Israeli Foundation for Scientific Research and Development	I-65-412.20-2016
Bundesministerium für Bildung und Forschung	01ZX1307, 01ZX1406, 01ZX1303, 01ZX1303A, 01GM1211B
Else Kröner-Fresenius-Stiftung	2016_Kolleg.19, 2014-A06
Ministerio de Economía y Competitividad	SAF2016-74855-P, SAF2013-43255-P
Israel Science Foundation
Deutsche Krebshilfe	1117240

Keywords

DNA damage
DNA double-strand break repair
UBQLN4 deficiency syndrome
cancer
genome instability syndrome
homologous recombination
non-homologous end joining
proteasomal degradation
targeted cancer therapy
ubiquitin

UN SDGs

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

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10.1016/j.cell.2018.11.024

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Jachimowicz, R. D., Beleggia, F., Isensee, J., Velpula, B. B., Goergens, J., Bustos, M. A., Doll, M. A., Shenoy, A., Checa-Rodriguez, C., Wiederstein, J. L., Baranes-Bachar, K., Bartenhagen, C., Hertwig, F., Teper, N., Nishi, T., Schmitt, A., Distelmaier, F., Lüdecke, H. J., Albrecht, B., ... Shiloh, Y. (2019). UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors. Cell, 176(3), 505-519.e22. https://doi.org/10.1016/j.cell.2018.11.024

@article{3144d03af93b4e2bb5e2a97453a1fe28,

title = "UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors",

abstract = "Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.",

keywords = "DNA damage, DNA double-strand break repair, UBQLN4 deficiency syndrome, cancer, genome instability syndrome, homologous recombination, non-homologous end joining, proteasomal degradation, targeted cancer therapy, ubiquitin",

author = "Jachimowicz, {Ron D.} and Filippo Beleggia and J{\"o}rg Isensee and Velpula, {Bhagya Bhavana} and Jonas Goergens and Bustos, {Matias A.} and Doll, {Markus A.} and Anjana Shenoy and Cintia Checa-Rodriguez and Wiederstein, {Janica Lea} and Keren Baranes-Bachar and Christoph Bartenhagen and Falk Hertwig and Nizan Teper and Tomohiko Nishi and Anna Schmitt and Felix Distelmaier and L{\"u}decke, {Hermann Josef} and Beate Albrecht and Marcus Kr{\"u}ger and Bj{\"o}rn Schumacher and Tamar Geiger and Hoon, {Dave S.B.} and Pablo Huertas and Matthias Fischer and Tim Hucho and Martin Peifer and Yael Ziv and Reinhardt, {H. Christian} and Dagmar Wieczorek and Yosef Shiloh",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

month = jan,

day = "24",

doi = "10.1016/j.cell.2018.11.024",

language = "אנגלית",

volume = "176",

pages = "505--519.e22",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier",

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Jachimowicz, RD, Beleggia, F, Isensee, J, Velpula, BB, Goergens, J, Bustos, MA, Doll, MA, Shenoy, A, Checa-Rodriguez, C, Wiederstein, JL, Baranes-Bachar, K, Bartenhagen, C, Hertwig, F, Teper, N, Nishi, T, Schmitt, A, Distelmaier, F, Lüdecke, HJ, Albrecht, B, Krüger, M, Schumacher, B, Geiger, T, Hoon, DSB, Huertas, P, Fischer, M, Hucho, T, Peifer, M, Ziv, Y, Reinhardt, HC, Wieczorek, D & Shiloh, Y 2019, 'UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors', Cell, vol. 176, no. 3, pp. 505-519.e22. https://doi.org/10.1016/j.cell.2018.11.024

TY - JOUR

T1 - UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

AU - Jachimowicz, Ron D.

AU - Beleggia, Filippo

AU - Isensee, Jörg

AU - Velpula, Bhagya Bhavana

AU - Goergens, Jonas

AU - Bustos, Matias A.

AU - Doll, Markus A.

AU - Shenoy, Anjana

AU - Checa-Rodriguez, Cintia

AU - Wiederstein, Janica Lea

AU - Baranes-Bachar, Keren

AU - Bartenhagen, Christoph

AU - Hertwig, Falk

AU - Teper, Nizan

AU - Nishi, Tomohiko

AU - Schmitt, Anna

AU - Distelmaier, Felix

AU - Lüdecke, Hermann Josef

AU - Albrecht, Beate

AU - Krüger, Marcus

AU - Schumacher, Björn

AU - Geiger, Tamar

AU - Hoon, Dave S.B.

AU - Huertas, Pablo

AU - Fischer, Matthias

AU - Hucho, Tim

AU - Peifer, Martin

AU - Ziv, Yael

AU - Reinhardt, H. Christian

AU - Wieczorek, Dagmar

AU - Shiloh, Yosef

PY - 2019/1/24

Y1 - 2019/1/24

N2 - Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.

AB - Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.

KW - DNA damage

KW - DNA double-strand break repair

KW - UBQLN4 deficiency syndrome

KW - cancer

KW - genome instability syndrome

KW - homologous recombination

KW - non-homologous end joining

KW - proteasomal degradation

KW - targeted cancer therapy

KW - ubiquitin

UR - http://www.scopus.com/inward/record.url?scp=85060092449&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.11.024

DO - 10.1016/j.cell.2018.11.024

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

AN - SCOPUS:85060092449

SN - 0092-8674

VL - 176

SP - 505-519.e22

JO - Cell

JF - Cell

IS - 3

ER -

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

Abstract

Funding

Keywords

UN SDGs

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