A role for Brca1 in chromosome end maintenance

Abstract

The role of BRCA1 in breast and ovarian tumor suppression has been primarily ascribed to the maintenance of genome integrity. BRCA1 interacts with components of the non-homologous end-joining pathway previously shown to play a role in telomere maintenance in yeast. Here, we provide evidence that links Brca1 with telomere integrity. Brca1(-/-) T-cells display telomere dysfunction in both loss of telomere repeats as well as defective telomere capping. Loss of Brca1 synergizes with p53 deficiency in the onset and frequency of tumorigenesis. Karyotyping of tBrca1(-/-)p53(-/-) thymic lymphomas revealed the presence of telomere dysfunction accompanied by clonal chromosomal translocations. The telomere dysfunction phenotype in Brca1-deficient cells suggests that loss of telomere integrity might contribute to chromosome end dysfunction and permit the formation of potentially oncogenic translocations.

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

“…BRCA1 is recruited to sites of stalled replication together with BRCA2, Rad51 and other recombination proteins, suggesting that this is part of a generic response of HR proteins to replication arrest. The idea that BRCA gene products have a significant HR function during the S phase was corroborated by the finding that chromosomes from BRCA mutant embryos develop "chromatid-type" structural aberrations [95,96]. This type of chromosomal rearrangement reflects asymmetric damage to sister chromatids and has traditionally been considered to arise from replication across a damaged DNA template and from recombination errors in S phase.…”

“…This review has not touched upon the contributions of BRCA1 and BRCA2 to checkpoint functions [150][151][152], transcriptional regulation [153,154], gene silencing [81,82,155], telomere function [96] or (for BARD1) mRNA processing [156,157]. Both HR and non-HR functions of BRCA genes might account for the tissue specificity of cancer risk in BRCA gene mutation carriers [158] and the latter may be important modulators of the clinical phenotypes associated with BRCA gene inactivation.…”

Haploinsufficiency of Parp1 accelerates Brca1-associated centrosome amplification, telomere shortening, genetic instability, apoptosis, and embryonic lethality

“…26 T cells derived from Brca1-deficient mice display telomere dysfunction characterized by both loss of telomere repeats and defective telomere capping. 27 This suggests that loss of telomere integrity owing to Brca1 deficiency might contribute to chromosome end dysfunction and permit the formation of potentially oncogenic translocations. By contrast, it has also been reported that disruption of BRCA1 function results in telomere elongation.…”

“…Recent studies implicated both BRCA1 and PARP1 in telomere maintenance and function, yet the actual role of BRCA1 remains controversial. 27,32,33 It has been shown that BRCA1 inhibits the expression of hTERT, the catalytic subunit of telomerase; therefore expression of wild-type BRCA1, but not a tumorassociated mutant BRCA1 (T300G), caused telomere shortening in human prostate and breast cancer cell lines. 33 In contrast, it was shown in mouse T cells that Brca1 deficiency results in telomere shortening that is characterized by the loss of telomere repeats and defective telomere capping.…”

Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers

“…These phenomena may be ascribed to the role that BRCA1 is thought to play in maintaining genomic integrity (1). Indeed, BRCA1 is involved in a plethora of cellular processes, including DNA damage response (1, 2), chromatin remodeling (3), XIST-dependent X-chromosome silencing (4), telomere protection (5,6), and transcription elongation (7). In particular, robust evidence indicates that BRCA1 is involved in homologous recombination-mediated DNA repair of double-strand breaks (1).…”