Gothe, Henrike Johanna, Bouwman, Britta Annika Maria, Gusmao, Eduardo Gade, Piccinno, Rossana, Petrosino, Giuseppe ORCID: 0000-0002-2835-4308, Sayols, Sergi ORCID: 0000-0002-3877-4170, Drechsel, Oliver, Minneker, Vera, Josipovic, Natasa, Mizi, Athanasia ORCID: 0000-0002-4313-491X, Nielsen, Christian Friberg ORCID: 0000-0002-2886-317X, Wagner, Eva-Maria, Takeda, Shunichi, Sasanuma, Hiroyuki, Hudson, Damien Francis, Kindler, Thomas, Baranello, Laura, Papantonis, Argyris ORCID: 0000-0001-7551-1073, Crosetto, Nicola and Roukos, Vassilis ORCID: 0000-0002-5065-3937 (2019). Spatial Chromosome Folding and Active Transcription Drive DNA Fragility and Formation of Oncogenic MLL Translocations. Mol. Cell, 75 (2). S. 267 - 296. CAMBRIDGE: CELL PRESS. ISSN 1097-4164

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Abstract

How spatial chromosome organization influences genome integrity is still poorly understood. Here, we show that DNA double-strand breaks (DSBs) mediated by topoisomerase 2 (TOP2) activities are enriched at chromatin loop anchors with high transcriptional activity. Recurrent DSBs occur at CCCTC-binding factor (CTCF) and cohesin-bound sites at the bases of chromatin loops, and their frequency positively correlates with transcriptional output and directionality. The physiological relevance of this preferential positioning is indicated by the finding that genes recurrently translocating to drive leukemias are highly transcribed and are enriched at loop anchors. These genes accumulate DSBs at recurrent hotspots that give rise to chromosomal fusions relying on the activity of both TOP2 isoforms and on transcriptional elongation. We propose that transcription and 3D chromosome folding jointly pose a threat to genomic stability and are key contributors to the occurrence of genome rearrangements that drive cancer.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gothe, Henrike JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouwman, Britta Annika MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gusmao, Eduardo GadeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piccinno, RossanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petrosino, GiuseppeUNSPECIFIEDorcid.org/0000-0002-2835-4308UNSPECIFIED
Sayols, SergiUNSPECIFIEDorcid.org/0000-0002-3877-4170UNSPECIFIED
Drechsel, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Minneker, VeraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Josipovic, NatasaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mizi, AthanasiaUNSPECIFIEDorcid.org/0000-0002-4313-491XUNSPECIFIED
Nielsen, Christian FribergUNSPECIFIEDorcid.org/0000-0002-2886-317XUNSPECIFIED
Wagner, Eva-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Takeda, ShunichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sasanuma, HiroyukiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hudson, Damien FrancisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kindler, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baranello, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papantonis, ArgyrisUNSPECIFIEDorcid.org/0000-0001-7551-1073UNSPECIFIED
Crosetto, NicolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roukos, VassilisUNSPECIFIEDorcid.org/0000-0002-5065-3937UNSPECIFIED
URN: urn:nbn:de:hbz:38-134690
DOI: 10.1016/j.molcel.2019.05.015
Journal or Publication Title: Mol. Cell
Volume: 75
Number: 2
Page Range: S. 267 - 296
Date: 2019
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4164
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TOPOISOMERASE-II-BETA; PROTEIN-KINASE INHIBITOR; DOUBLE-STRAND BREAKS; HISTONE MODIFICATIONS; GENOME; ARCHITECTURE; EXPRESSION; LEUKEMIA; CLEAVAGE; REGIONSMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13469

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