APOBEC3A is a prominent cytidine deaminase in breast cancer


Autoři: Luis M. Cortez aff001;  Amber L. Brown aff001;  Madeline A. Dennis aff001;  Christopher D. Collins aff001;  Alexander J. Brown aff001;  Debra Mitchell aff001;  Tony M. Mertz aff001;  Steven A. Roberts aff001
Působiště autorů: School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, WA, United States of America aff001;  Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, United States of America aff002;  School of Molecular Biosciences, Washington State University-Vancouver, Vancouver, WA, United States of America aff003
Vyšlo v časopise: APOBEC3A is a prominent cytidine deaminase in breast cancer. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008545
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008545

Souhrn

APOBEC cytidine deaminases are the second-most prominent source of mutagenesis in sequenced tumors. Previous studies have proposed that APOBEC3B (A3B) is the major source of mutagenesis in breast cancer (BRCA). We show that APOBEC3A (A3A) is the only APOBEC whose expression correlates with APOBEC-induced mutation load and that A3A expression is responsible for cytidine deamination in multiple BRCA cell lines. Comparative analysis of A3A and A3B expression by qRT-PCR, RSEM-normalized RNA-seq, and unambiguous RNA-seq validated the use of RNA-seq to measure APOBEC expression, which indicates that A3A is the primary correlate with APOBEC-mutation load in primary BRCA tumors. We also demonstrate that A3A has >100-fold more cytidine deamination activity than A3B in the presence of cellular RNA, likely explaining why higher levels of A3B expression contributes less to mutagenesis in BRCA. Our findings identify A3A as a major source of cytidine deaminase activity in breast cancer cells and possibly a prominent contributor to the APOBEC mutation signature.

Klíčová slova:

BT474 cells – Gene expression – Genetic causes of cancer – Haplotypes – Mutagenesis – RNA extraction – RNA sequencing – Sequence motif analysis


Zdroje

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Genetika Reprodukční medicína

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PLOS Genetics


2019 Číslo 12

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