Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence

Abstract

Although BRCA1 function is essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer in individuals harbouring deleterious mutations in BRCA1 is restricted to only a select few tissues. Here we show that human mammary epithelial cells (HMECs) from BRCA1-mutation carriers (BRCA1mut/+) exhibit increased genomic instability and rapid telomere erosion in the absence of tumour-suppressor loss. Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction. HIS and telomere erosion in HMECs correlate with misregulation of SIRT1 leading to increased levels of acetylated pRb as well as acetylated H4K16 both globally and at telomeric regions. These results identify a novel form of cellular senescence and provide a potential molecular basis for the rapid cell- and tissue- specific predisposition of breast cancer development associated with BRCA1 haploinsufficiency.

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

“…Both the observed methylation and expression abnormalities may be due to perturbations of a superordinate mechanism, which predisposes to mutation‐negative EO and HR BC. Accumulating evidence suggests that mutations in a single BRCA1 allele are sufficient to alter the phenotype of breast epithelial cells, leading to cell‐type specific genomic instability and premature senescence 38, 39. In this light, it is plausible to assume that haploinsufficiency of BRCA1 and other tumor suppressor genes confers an increased BC risk.…”

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

“…BRCA1 is involved in DNA damage repair through nonhomologous end joining (NHEJ) and homologous recombination (HR) (Moynahan et al, 1999; Cao et al, 2003; Davalos and Campisi, 2003; Ohta et al, 2011). The lack of functional BRCA1 leads to radiosensitivity and telomere dysfunction (Foray et al, 1999; Trenz et al, 2002; Acharya et al, 2014; Sedic et al, 2015). The DNA damage sensor, the MRN complex, usually recruits BRCA1 to the DNA damage sites (Rosen, 2013).…”

“…In a recent study, it was shown that primary human mammary epithelial cells (HMECs) with mutations in BRCA1 ( mut/+ ) show premature senescence as a result of genomic instability (Sedic et al, 2015). This unique type of cellular senescence caused by haploinsufficiency of a tumor suppressor is termed haploinsufficiency‐induced senescence (HIS) (Sedic et al, 2015). The spontaneous bypass of this senescence pathway is thought to be involved in the early onset of breast cancer in individuals with BRCA1 mutations (Sedic et al, 2015).…”

“…This unique type of cellular senescence caused by haploinsufficiency of a tumor suppressor is termed haploinsufficiency‐induced senescence (HIS) (Sedic et al, 2015). The spontaneous bypass of this senescence pathway is thought to be involved in the early onset of breast cancer in individuals with BRCA1 mutations (Sedic et al, 2015). Although these immortalized nontumorigenic BRCA1 mut/+ HMECs showed rapid genomic instability, increased DNA damage and telomere erosion, the exact mechanism by which the telomere maintenance is affected is not known (Sedic et al, 2015).…”

“…The spontaneous bypass of this senescence pathway is thought to be involved in the early onset of breast cancer in individuals with BRCA1 mutations (Sedic et al, 2015). Although these immortalized nontumorigenic BRCA1 mut/+ HMECs showed rapid genomic instability, increased DNA damage and telomere erosion, the exact mechanism by which the telomere maintenance is affected is not known (Sedic et al, 2015). Recent findings suggest that BRCA1 accumulates at telomeres in the ALT‐positive cancer cells, most likely with the help of BLM and PML bodies (Acharya et al, 2014).…”