Abstract |
Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF ( CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/ cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.
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Authors | Riku Katainen, Kashyap Dave, Esa Pitkänen, Kimmo Palin, Teemu Kivioja, Niko Välimäki, Alexandra E Gylfe, Heikki Ristolainen, Ulrika A Hänninen, Tatiana Cajuso, Johanna Kondelin, Tomas Tanskanen, Jukka-Pekka Mecklin, Heikki Järvinen, Laura Renkonen-Sinisalo, Anna Lepistö, Eevi Kaasinen, Outi Kilpivaara, Sari Tuupanen, Martin Enge, Jussi Taipale, Lauri A Aaltonen |
Journal | Nature genetics
(Nat Genet)
Vol. 47
Issue 7
Pg. 818-21
(Jul 2015)
ISSN: 1546-1718 [Electronic] United States |
PMID | 26053496
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- CCCTC-Binding Factor
- CTCF protein, human
- Cell Cycle Proteins
- Chromosomal Proteins, Non-Histone
- Repressor Proteins
- cohesins
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Topics |
- Binding Sites
- CCCTC-Binding Factor
- Cell Cycle Proteins
(physiology)
- Chromosomal Proteins, Non-Histone
(physiology)
- Colorectal Neoplasms
- Consensus Sequence
- Genetic Association Studies
- Genetic Predisposition to Disease
- Humans
- Point Mutation
- Regulatory Sequences, Nucleic Acid
- Repressor Proteins
(physiology)
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