REAGENT or RESOURCE	SOURCE	IDENTIFIER
Antibodies
Rpb1 NTD (D8L4Y) antibody	Cell Signaling Tech.	Cat# 14958; RRID:AB_2687876
Rabbit monoclonal antibody against Topoisomerase II Alpha (Topo IIa)(EP1102Y)	Abcam	Cat# ab52934; RRID:AB_2240762
Anti-Topo IIalpha (F-12) antibody	Santa Cruz Biotech.	Cat# sc-365916; RRID:AB_10842059
TOP2B antibody	Proteintech	Cat# 20549-1-AP; RRID:AB_10700004
Topoisomerase I antibody - ChIP Grade	Abcam	Cat# ab3825; RRID:AB_304095
Topoisomerase I antibody [EPR5375]	Abcam	Cat# ab109374; RRID:AB_10861978
Anti-p38 MAPK, phospho (Thr180 / Tyr182) Antibody, Unconjugated	Cell Signaling Tech.	Cat# 9211; RRID:AB_331641
Anti-α-Tubulin antibody	Sigma-Aldrich	Cat# T9026; RRID:AB_477593
Mouse Anti-Histone H2A.X, phospho (Ser139) Monoclonal antibody, Unconjugated, Clone jbw301	Millipore	Cat# 05-636; RRID:AB_309864
Rabbit Anti-Histone H3, phospho (Ser10) Mitosismarker Polyclonal antibody, Unconjugated	Millipore	Cat# 06-570; RRID:AB_310177
NELF-E (H-140) antibody	Santa Cruz Biotech.	Cat# sc-32912; RRID:AB_2177858
Bacterial and virus strains
e. coli: stbl3 competent cells	This paper	N/A
e. coli: DH5α competent cells	This paper	N/A
Chemicals, peptides, and recombinant proteins
EZ-Link Psoralen-PEG3-Biotin	Thermo Fisher	Cat# 29986
Digitonin	Sigma-Aldrich	Cat# D141
Tn5A Enzyme	CABD	N/A
s.p. Cas9 Nuclease 3NLS	Integrated DNA Tech.	Cat# 1074181
Merbarone	Sigma-Aldrich	Cat# M2070
Etoposide	Sigma-Aldrich	Cat# E1383
ICRF-187	Sigma-Aldrich	Cat# D1446
Camptothecin	Sigma-Aldrich	Cat# C9911
Triptolide	Sigma-Aldrich	Cat#T3652
Critical commercial assays
DuoLink PLA Kit	Sigma-Aldrich	Cat# DUO92008100RXN
RNeasy KIT	QIAGEN	Cat# 74106
TruSeq Stranded mRNA	lllumina	Cat# 20020594
Deposited data
RNA sequencing Data	This paper	GEO: GSE141800
ChIP-seq data of TOP2A	This paper	GEO: GSE141800
ChIP-seq data of POL2	This paper	GEO: GSE141800
CTCF ChIP-seq	ENCODE Project Consortium, 2012	https://www.encodeproject.org/experiments/ENCSR000DVI/
H3K4me3 ChIP-seq	ENCODE Project Consortium, 2012	https://www.encodeproject.org/experiments/ENCSR000DVK/
H3K27ac ChIP-seq	Sánchez et al., 2018	https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM2865066
Human reference genome, NCBI build 37, GRCh37/hg19	Genome Reference Consortium	https://www.ncbi.nlm.nih.gov/grc/human
Unprocessed and uncompressed imaging data (microscopy and blots)	This paper	Mendeley Data at: http://dx.doi.org/10.17632/r69w5y36w2.1
Experimental models: Cell lines
hTERT-RPE-1 cells	ATCC	CRL-4000
Cas9-overexpressing hTERT RPE-1	Kindly provided byDr. Durocher Lab	N/A
A549	ATCC	CCL-185
HEK293T	ATCC	CRL-1573
U2OS	ATCC	HTB-96
Mouse Embryonic Fibroblast (MEFs)	This paper	N/A
Oligonucleotides
Primers for qPCR, see Table S1	This paper	N/A
siRNA targeting sequence: NELFE: GGCAUUGCUGGCUCUGAAGUU	Aiyar et al., 2004	N/A
siRNA targeting sequence: LUC: CGUACGCGGAAUACUUCGA	Jimeno-González et al., 2015	N/A
CRISPR-Cas9 tracrRNA	Integrated DNA Tech.	Cat# 1072532
crRNAs targeting sequence: TOP2A:CTCCGCCCAGACACCTACAT	This paper	N/A
crRNAs targeting sequence:TOP2B: CTTCGTCCTGATACATATAT	This paper	N/A
crRNAs targeting sequence: TDP2:CTTGCTGAGTATCTTCAGAT	This paper	N/A
crRNAs targeting sequence: FOS 1#:ACTAGCACTGTTCCTGCGTT	This paper	N/A
crRNAs targeting sequence: FOS 2#:CCCTAATTCAGTGCAAAGCG	This paper	N/A
crRNAs targeting sequence: Non-targeting	Integrated DNA Tech.	Cat# 1072544
Recombinant DNA
lentiCas9n(D10A)-Blast plasmid	Sanjana et al., 2014	Addgene Plasmid #63593
Software and algorithms
GraphPad Prism 8	GraphPad	N/A
R version 3.5.0	R Core Team, 2018	https://www.R-project.org/
FASTQC	Andrews, 2010	https://www.bioinformatics.babraham.ac.uk/projects/fastqc/
Bowtie version 1.2.0	Langmead et al., 2009	http://bowtie-bio.sourceforge.net/index.shtml
MACS2 version 2.1	Zhang et al., 2008	https://github.com/macs3-project/MACS
DESeq2	Love et al., 2014	https://bioconductor.org/packages/release/bioc/html/DESeq2.html