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Article ; Online: Pathways for maintenance of telomeres and common fragile sites during DNA replication stress

Özgün Özer / Ian D. Hickson

Open Biology, Vol 8, Iss

2018 Volume 4

Abstract: Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA ... ...

Abstract	Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently ‘difficult-to-replicate’ nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed ‘mitotic DNA repair synthesis (MiDAS)’, to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into how MiDAS helps cells to counteract DNA replication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.
Keywords	alternative lengthening of telomeres ; common fragile sites ; rad52 ; homologous recombination ; cancer ; Biology (General) ; QH301-705.5
Subject code	612 ; 570
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	The Royal Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The "enemies within"

Rahul Bhowmick / Ian D Hickson

F1000Research, Vol

regions of the genome that are inherently difficult to replicate [version 1; referees: 2 approved]

2017 Volume 6

Abstract: An unusual feature of many eukaryotic genomes is the presence of regions that appear intrinsically difficult to copy during the process of DNA replication. Curiously, the location of these difficult-to-replicate regions is often conserved between species, ...

Abstract	An unusual feature of many eukaryotic genomes is the presence of regions that appear intrinsically difficult to copy during the process of DNA replication. Curiously, the location of these difficult-to-replicate regions is often conserved between species, implying a valuable role in some aspect of genome organization or maintenance. The most prominent class of these regions in mammalian cells is defined as chromosome fragile sites, which acquired their name because of a propensity to form visible gaps/breaks on otherwise-condensed chromosomes in mitosis. This fragility is particularly apparent following perturbation of DNA replication—a phenomenon often referred to as “replication stress”. Here, we review recent data on the molecular basis for chromosome fragility and the role of fragile sites in the etiology of cancer. In particular, we highlight how studies on fragile sites have provided unexpected insights into how the DNA repair machinery assists in the completion of DNA replication.
Keywords	Cell Growth & Division ; Cellular Death & Stress Responses ; Control of Gene Expression ; Genomics ; Medical Genetics ; Nuclear Structure & Function ; Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2017-05-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Inducible Degradation of the Human SMC5/6 Complex Reveals an Essential Role Only during Interphase

Andrés Bueno Venegas / Toyoaki Natsume / Masato Kanemaki / Ian D. Hickson

Cell Reports, Vol 31, Iss 3, Pp - (2020)

2020

Abstract: Summary: The cohesin- and condensin-related SMC5/6 complex has largely been studied in the context of DNA repair. Nevertheless, SMC5/6 has an undefined essential function even in the absence of cellular stress. Through the use of an auxin-inducible ... ...

Abstract	Summary: The cohesin- and condensin-related SMC5/6 complex has largely been studied in the context of DNA repair. Nevertheless, SMC5/6 has an undefined essential function even in the absence of cellular stress. Through the use of an auxin-inducible degradation system for rapidly depleting subunits of the SMC5/6 complex, we show that SMC5/6 is essential for viability in cancer-derived and normal human cells. Impairment of SMC5/6 function is associated with spontaneous induction of DNA damage, p53 activation, cell-cycle arrest, and senescence, as well as an increased frequency of various mitotic chromosome segregation abnormalities. However, we show that this chromosome missegregation is apparent only when SMC5/6 function is impaired during the preceding S and G2 phases. In contrast, degradation of SMC5/6 immediately prior to mitotic entry has little or no impact on the fidelity of chromosome segregation, highlighting the importance of the complex during interphase in order to ensure faithful sister chromatid disjunction. : Venegas et al. employ an auxin-inducible degron system for different subunits of the SMC5/6 complex to interrogate the short- and long-term effects of SMC5/6 impairment in human cells. Degradation of SMC5/6’s subunits at different cell cycle stages places the essential role of the complex during S phase.
Keywords	Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: TRAIP drives replisome disassembly and mitotic DNA repair synthesis at sites of incomplete DNA replication

Remi Sonneville / Rahul Bhowmick / Saskia Hoffmann / Niels Mailand / Ian D Hickson / Karim Labib

eLife, Vol

2019 Volume 8

Abstract: The faithful segregation of eukaryotic chromosomes in mitosis requires that the genome be duplicated completely prior to anaphase. However, cells with large genomes sometimes fail to complete replication during interphase and instead enter mitosis with ... ...

Abstract	The faithful segregation of eukaryotic chromosomes in mitosis requires that the genome be duplicated completely prior to anaphase. However, cells with large genomes sometimes fail to complete replication during interphase and instead enter mitosis with regions of incompletely replicated DNA. These regions are processed in early mitosis via a process known as mitotic DNA repair synthesis (MiDAS), but little is known about how cells switch from conventional DNA replication to MiDAS. Using the early embryo of the nematode Caenorhabditis elegans as a model system, we show that the TRAIP ubiquitin ligase drives replisome disassembly in response to incomplete DNA replication, thereby providing access to replication forks for other factors. Moreover, TRAIP is essential for MiDAS in human cells, and is important in both systems to prevent mitotic segregation errors. Our data indicate that TRAIP is a master regulator of the processing of incomplete DNA replication during mitosis in metazoa.
Keywords	DNA replication ; genome stability ; ubiquitin ligase ; TRAIP ; mitosis ; fragile site ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PICH acts as a force-dependent nucleosome remodeler

Dian Spakman / Tinka V. M. Clement / Andreas S. Biebricher / Graeme A. King / Manika I. Singh / Ian D. Hickson / Erwin J. G. Peterman / Gijs J. L. Wuite

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 12

Abstract: In anaphase, any unresolved DNA entanglements between the segregating sister chromatids can give rise to chromatin bridges. Here, the authors present an in vitro single-molecule assay that mimics chromatin under tension, to show that PICH is a tension- ... ...

Abstract	In anaphase, any unresolved DNA entanglements between the segregating sister chromatids can give rise to chromatin bridges. Here, the authors present an in vitro single-molecule assay that mimics chromatin under tension, to show that PICH is a tension- and ATP-dependent nucleosome remodeler.
Keywords	Science ; Q
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PICH Supports Embryonic Hematopoiesis by Suppressing a cGAS‐STING‐Mediated Interferon Response

Xinwei Geng / Chao Zhang / Miao Li / Jiaqi Wang / Fang Ji / Hanrong Feng / Meichun Xing / Fei Li / Lingling Zhang / Wen Li / Zhihua Chen / Ian D. Hickson / Huahao Shen / Songmin Ying

Advanced Science, Vol 9, Iss 7, Pp n/a-n/a (2022)

2022

Abstract: Abstract The Plk1‐interacting checkpoint helicase (PICH) protein localizes to ultrafine anaphase DNA bridges in mitosis along with a complex of DNA repair proteins. Previous studies show PICH deficiency‐induced embryonic lethality in mice. However, the ... ...

Abstract	Abstract The Plk1‐interacting checkpoint helicase (PICH) protein localizes to ultrafine anaphase DNA bridges in mitosis along with a complex of DNA repair proteins. Previous studies show PICH deficiency‐induced embryonic lethality in mice. However, the function of PICH that is required to suppress embryonic lethality in PICH‐deficient mammals remains to be determined. Previous clinical studies suggest a link between PICH deficiency and the onset of acquired aplastic anemia. Here, using Pich knock‐out (KO) mouse models, the authors provide evidence for a mechanistic link between PICH deficiency and defective hematopoiesis. Fetal livers from Pich‐KO embryos exhibit a significantly elevated number of hematopoietic stem cells (HSCs); however, these HSCs display a higher level of apoptosis and a much‐reduced ability to reconstitute a functional hematopoietic system when transplanted into lethally irradiated recipients. Moreover, these HSCs show an elevated cytoplasmic dsDNA expression and an activation of the cGAS‐STING pathway, resulting in excessive production of type I interferons (IFN). Importantly, deletion of Ifnar1 or cGAS reverses the defective hematopoiesis. The authors conclude that loss of PICH results in defective hematopoiesis via cGAS‐STING‐mediated type I IFN production.
Keywords	cGAS‐STING ; genomic stability ; hematopoietic stem cells ; Plk1‐interacting checkpoint helicase ; type I interferons ; Science ; Q
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Duplex DNA and BLM regulate gate opening by the human TopoIIIα-RMI1-RMI2 complex

Julia A. M. Bakx / Andreas S. Biebricher / Graeme A. King / Panagiotis Christodoulis / Kata Sarlós / Anna H. Bizard / Ian D. Hickson / Gijs J. L. Wuite / Erwin J. G. Peterman

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 13

Abstract: Here the authors probe the cleavage and gate opening of single-stranded DNA by the human topoisomerase TRR using a unique single-molecule strategy to reveal structural plasticity in response to both double-stranded DNA and the helicase BLM. ...

Abstract	Here the authors probe the cleavage and gate opening of single-stranded DNA by the human topoisomerase TRR using a unique single-molecule strategy to reveal structural plasticity in response to both double-stranded DNA and the helicase BLM.
Keywords	Science ; Q
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress

Bhowmick, Rahul / Ian D. Hickson / Sheroy Minocherhomji

Molecular cell. 2016 Dec. 15, v. 64, no. 6

2016

Abstract: Homologous recombination (HR) is necessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitive to replication stress and undergo pathological rearrangements in tumors. At these loci, replication stress ... ...

Abstract	Homologous recombination (HR) is necessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitive to replication stress and undergo pathological rearrangements in tumors. At these loci, replication stress frequently activates DNA repair synthesis in mitosis. This mitotic DNA synthesis, termed MiDAS, requires the MUS81-EME1 endonuclease and a non-catalytic subunit of the Pol-delta complex, POLD3. Here, we examine the contribution of HR factors in promoting MiDAS in human cells. We report that RAD51 and BRCA2 are dispensable for MiDAS but are required to counteract replication stress at CFS loci during S-phase. In contrast, MiDAS is RAD52 dependent, and RAD52 is required for the timely recruitment of MUS81 and POLD3 to CFSs in early mitosis. Our results provide further mechanistic insight into MiDAS and define a specific function for human RAD52. Furthermore, selective inhibition of MiDAS may comprise a potential therapeutic strategy to sensitize cancer cells undergoing replicative stress.
Keywords	DNA ; DNA repair ; DNA replication ; homologous recombination ; humans ; loci ; mitosis ; neoplasm cells ; neoplasms ; tumor suppressor proteins
Language	English
Dates of publication	2016-1215
Size	p. 1117-1126.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2016.10.037
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: MicroRNA-449a Inhibits Triple Negative Breast Cancer by Disturbing DNA Repair and Chromatid Separation

Beate Vajen / Rahul Bhowmick / Luisa Greiwe / Vera Schäffer / Marlies Eilers / Thea Reinkens / Amelie Stalke / Gunnar Schmidt / Jan Fiedler / Thomas Thum / David S. DeLuca / Ian D. Hickson / Brigitte Schlegelberger / Thomas Illig / Britta Skawran

International Journal of Molecular Sciences, Vol 23, Iss 5131, p

2022 Volume 5131

Abstract: Chromosomal instability (CIN) can be a driver of tumorigenesis but is also a promising therapeutic target for cancer associated with poor prognosis such as triple negative breast cancer (TNBC). The treatment of TNBC cells with defects in DNA repair genes ...

Abstract	Chromosomal instability (CIN) can be a driver of tumorigenesis but is also a promising therapeutic target for cancer associated with poor prognosis such as triple negative breast cancer (TNBC). The treatment of TNBC cells with defects in DNA repair genes with poly(ADP-ribose) polymerase inhibitor (PARPi) massively increases CIN, resulting in apoptosis. Here, we identified a previously unknown role of microRNA-449a in CIN. The transfection of TNBC cell lines HCC38, HCC1937 and HCC1395 with microRNA-449a mimics led to induced apoptosis, reduced cell proliferation, and reduced expression of genes in homology directed repair (HDR) in microarray analyses. EME1 was identified as a new target gene by immunoprecipitation and luciferase assays. The reduced expression of EME1 led to an increased frequency of ultrafine bridges, 53BP1 foci, and micronuclei. The induced expression of microRNA-449a elevated CIN beyond tolerable levels and induced apoptosis in TNBC cell lines by two different mechanisms: (I) promoting chromatid mis-segregation by targeting endonuclease EME1 and (II) inhibiting HDR by downregulating key players of the HDR network such as E2F3 , BIRC5 , BRCA2 and RAD51 . The ectopic expression of microRNA-449a enhanced the toxic effect of PARPi in cells with pathogenic germline BRCA1 variants. The newly identified role makes microRNA-449a an interesting therapeutic target for TNBC.
Keywords	microRNA449a ; triple negative breast cancer ; DNA repair ; chromosomal instability ; chromatid separation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616 ; 610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Loss of PICH Results in Chromosomal Instability, p53 Activation, and Embryonic Lethality

Eliene Albers / Mauro Sbroggiò / David Pladevall-Morera / Anna H. Bizard / Alexandra Avram / Patricia Gonzalez / Javier Martin-Gonzalez / Ian D. Hickson / Andres J. Lopez-Contreras

Cell Reports, Vol 24, Iss 12, Pp 3274-

2018 Volume 3284

Abstract: Summary: PICH is a DNA translocase necessary for the resolution of ultrafine anaphase DNA bridges and to ensure the fidelity of chromosomal segregation. Here, we report the generation of an animal model deficient for PICH that allowed us to investigate ... ...

Abstract	Summary: PICH is a DNA translocase necessary for the resolution of ultrafine anaphase DNA bridges and to ensure the fidelity of chromosomal segregation. Here, we report the generation of an animal model deficient for PICH that allowed us to investigate its physiological relevance. Pich KO mice lose viability during embryonic development due to a global accumulation of DNA damage. However, despite the presence of chromosomal instability, extensive p53 activation, and increased apoptosis throughout the embryo, Pich KO embryos survive until day 12.5 of embryonic development. The absence of p53 failed to improve the viability of the Pich KO embryos, suggesting that the observed developmental defects are not solely due to p53-induced apoptosis. Moreover, Pich-deficient mouse embryonic fibroblasts exhibit chromosomal instability and are resistant to RASV12/E1A-induced transformation. Overall, our data indicate that PICH is essential to preserve chromosomal integrity in rapidly proliferating cells and is therefore critical during embryonic development and tumorigenesis. : Albers et al. show that PICH is essential for mouse embryonic development and that PICH deficiency limits oncogenic-induced cellular transformation. These findings suggest that PICH activity is critical during events requiring rapid cell proliferation such as embryonic development and tumorigenesis. Keywords: Pich, Ercc6l, ultrafine anaphase DNA bridges, UFBs, genomic instability, DNA damage, X chromosome inactivation
Keywords	Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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