53BP1 nuclear body-marked replication stress in a human mammary cell model of BRCA2 deficiency

BioRxiv : the Preprint Server for Biology
Weiran Feng, Maria Jasin

Abstract

BRCA2 deficiency causes genome instability and breast and ovarian cancer predisposition, but also paradoxically promotes cell lethality. The nature of the acute, detrimental consequences of BRCA2 loss is not fully understood. We recently generated BRCA2 conditional models from a non-transformed human mammary cell line, through allele-specific gene targeting using CRISPR-Cas9, which we now describe. With these models, we discovered that BRCA2 deficiency triggers a DNA under replication-53BP1 nuclear body formation-G1 arrest axis due to homologous recombination defects. In this Extra-view, we extend these findings to show that 53BP1 nuclear bodies are spatially linked with downstream p53 activation. Replication stress that leads to common fragile site expression to induce 53BP1 nuclear body formation is aggravated by the loss of BRCA2. Additionally, replication stress that does not selectively lead to common fragile site expression is also able to induce 53BP1 nuclear body formation in BRCA2-deficient cells, indicating lesions form more globally throughout the genome. Furthermore, compromising replication fork reversal by SMARCAL1 depletion restores replication fork protection but does not diminish the high replication stress in ...Continue Reading

Related Concepts

Alleles
Breast
DNA
Face
Genome
Ovarian Carcinoma
Recombination, Genetic
Virus Replication
Protein p53
Downstream

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