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XPD protects CTCF-Cohesin binding sites from somatic mutagenesis

Jayne A. Barbour, Tong Ou, Hu Fang, Noel C. Yue, Xiaoqiang Zhu, Michelle W. Wong-Brown, Haocheng Yang, Yuen T. Wong, Nikola A. Bowden, Song Wu, Jason W. H. Wong
doi: https://doi.org/10.1101/2022.01.21.477237
Jayne A. Barbour
1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
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Tong Ou
2Urology Institute of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China
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Hu Fang
1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
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Noel C. Yue
1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
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Xiaoqiang Zhu
1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
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Michelle W. Wong-Brown
3Centre for Drug Repurposing and Medicines Research, University of Newcastle, NSW, Australia
4Hunter Medical Research Institute, Newcastle, NSW, Australia
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Haocheng Yang
1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
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Yuen T. Wong
5Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, NSW, Australia
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Nikola A. Bowden
3Centre for Drug Repurposing and Medicines Research, University of Newcastle, NSW, Australia
4Hunter Medical Research Institute, Newcastle, NSW, Australia
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Song Wu
2Urology Institute of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China
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  • For correspondence: jwhwong@hku.hk wusong@szu.edu.cn
Jason W. H. Wong
1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
6Centre for PanorOmic Sciences, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
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  • For correspondence: jwhwong@hku.hk wusong@szu.edu.cn
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Abstract

Xeroderma pigmentosum group D (XPD) is a DNA helicase involved in transcription initiation and nucleotide excision repair. Missense mutations in XPD are putative drivers in bladder cancer (BLCA) and are associated with a specific single base substitution mutational signature. However, the impact of XPD on the genome-wide distribution of somatic mutations remains unexplored. We analysed somatic mutation distribution in whole-genome sequenced (WGS) BLCA samples with (XPD mutant) and without XPD mutations (WT). XPD genotype had a large impact on the distribution of somatic mutations. XPD mutant samples had increased mutation density at open chromatin, including striking mutation hotspots at CTCF-cohesin binding sites (CBS). We validate these findings in additional WGS cohorts and BLCA exomes. Analysis of XPD occupancy and CBS hotspot mutations in other cancer types suggest that XPD protects CBS from DNA damage. Our study implicates XPD in genomic integrity maintenance at topologically-associating domain boundaries marked by CTCF-cohesin binding.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 21, 2022.
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XPD protects CTCF-Cohesin binding sites from somatic mutagenesis
Jayne A. Barbour, Tong Ou, Hu Fang, Noel C. Yue, Xiaoqiang Zhu, Michelle W. Wong-Brown, Haocheng Yang, Yuen T. Wong, Nikola A. Bowden, Song Wu, Jason W. H. Wong
bioRxiv 2022.01.21.477237; doi: https://doi.org/10.1101/2022.01.21.477237
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XPD protects CTCF-Cohesin binding sites from somatic mutagenesis
Jayne A. Barbour, Tong Ou, Hu Fang, Noel C. Yue, Xiaoqiang Zhu, Michelle W. Wong-Brown, Haocheng Yang, Yuen T. Wong, Nikola A. Bowden, Song Wu, Jason W. H. Wong
bioRxiv 2022.01.21.477237; doi: https://doi.org/10.1101/2022.01.21.477237

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