Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

Abstract

Telomeres are specialized structures responsible for the chromosome end protection. Previous studies have revealed that defective BRCA1 may lead to elevated telomere fusions and accelerated telomere shortening. In addition, BRCA1 associates with promyelocytic leukemia (PML) bodies in alternative lengthening of telomeres (ALTs) positive cells. We report here elevated recombination rates at telomeres in cells from human BRCA1 mutation carriers and in mouse embryonic stem cells lacking both copies of functional Brca1. An increased recombination rate at telomeres is one of the signs of ALT. To investigate this possibility further we employed the C‐circle assay that identifies ALT unequivocally. Our results revealed elevated levels of ALT activity in Brca1 defective mouse cells. Similar results were obtained when the same cells were assayed for the presence of another ALT marker, namely the frequency of PML bodies. These results suggest that BRCA1 may act as a repressor of ALT. © 2016 The Authors Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

The Molecular Mechanisms and Therapeutic Prospects of Alternative Lengthening of Telomeres (ALT)

“…The inhibition of the SMC5/6 complex prevents telomere HR which results in the shortening of the cell’s telomeres and the cell’s eventual entrance into senescence [ 49 ]. RPA, BRCA1, BLM, FANCM, WRN, and the SLX1/SLX4/ERCC4 complex comprise additional targets with the inhibition of RPA, BLM, WRN, and FANCM (particularly when co-depleted with BLM) and the overexpression of BRCA1 and SLX1/SLX4/ERCC4 being most promising [ 51 , 122 , 124 , 125 , 157 , 158 , 159 , 160 , 161 ].…”