APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer

Abstract

SummaryEstrogen receptor α (ERα) is the key transcriptional driver in a large proportion of breast cancers. We report that APOBEC3B (A3B) is required for regulation of gene expression by ER and acts by causing C-to-U deamination at ER binding regions. We show that these C-to-U changes lead to the generation of DNA strand breaks through activation of base excision repair (BER) and to repair by non-homologous end-joining (NHEJ) pathways. We provide evidence that transient cytidine deamination by A3B aids chromatin modification and remodelling at the regulatory regions of ER target genes that promotes their expression. A3B expression is associated with poor patient survival in ER+ breast cancer, reinforcing the physiological significance of A3B for ER action.

GIGGLE: a search engine for large-scale integrated genome analysis

“…2d) uncovers sequence-specific transcription factors known to play important roles in ER genomic binding (FOXA1 16 , GATA3 17 and PR 18 ) and cofactors that are involved in estrogen-induced gene regulation (EP300 19 and NCAPG 20 ). One unexpected finding from this large-scale analysis of MCF-7 ChIP-seq data is the strong co-occurrence of histone variant H2AFX 20,21 and ER cofactor GREB1 22 (Group 3 in Supplementary Fig. 2), suggesting a potential physical interaction between these factors.…”

Physiological functions of programmed DNA breaks in signal-induced transcription

“…The enzyme acts by mediating C-to-U changes that lead to the generation of DNA strand breaks through activation of the base excision repair (BER) pathway. DSB repair and the accompanying chromatin remodelling aid the expression of ERα target genes 56 . In B cells, AID proteins are recruited to super-enhancers and clusters of regulatory elements, and they promote DSB formation at these highly transcribed units 57 .…”

GIGGLE: a search engine for large-scale integrated genome analysis

“…Focusing specifically on ER (Figure 2d) uncovers sequence-specific transcription factors known to play important roles in ER genomic binding (FOXA1 16 , GATA3 17 and PR 18 ) and co-factors that are involved in estrogen-induced gene regulation (EP300 19 and NCAPG 20 ). One unexpected finding from this large-scale analysis of MCF-7 ChIP-seq data is the strong co-occurrence of histone variant H2AFX 20,21 and ER co-factor GREB1 22 (Group 3 in Supplemental Figure 2), suggesting a potential physical interaction between these factors.…”