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Shaping the BRCAness mutational landscape by alternative double-strand break repair, replication stress and mitotic aberrancies
- Source :
- Nucleic Acids Research, Nucleic Acids Research, 49(8), 4239-4257. Oxford University Press
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Abstract
- Tumours with mutations in the BRCA1/BRCA2 genes have impaired double-stranded DNA break repair, compromised replication fork protection and increased sensitivity to replication blocking agents, a phenotype collectively known as ‘BRCAness’. Tumours with a BRCAness phenotype become dependent on alternative repair pathways that are error-prone and introduce specific patterns of somatic mutations across the genome. The increasing availability of next-generation sequencing data of tumour samples has enabled identification of distinct mutational signatures associated with BRCAness. These signatures reveal that alternative repair pathways, including Polymerase θ-mediated alternative end-joining and RAD52-mediated single strand annealing are active in BRCA1/2-deficient tumours, pointing towards potential therapeutic targets in these tumours. Additionally, insight into the mutations and consequences of unrepaired DNA lesions may also aid in the identification of BRCA-like tumours lacking BRCA1/BRCA2 gene inactivation. This is clinically relevant, as these tumours respond favourably to treatment with DNA-damaging agents, including PARP inhibitors or cisplatin, which have been successfully used to treat patients with BRCA1/2-defective tumours. In this review, we aim to provide insight in the origins of the mutational landscape associated with BRCAness by exploring the molecular biology of alternative DNA repair pathways, which may represent actionable therapeutic targets in in these cells.
- Subjects :
- DNA Repair
DNA repair
AcademicSubjects/SCI00010
Antineoplastic Agents
Biology
Poly(ADP-ribose) Polymerase Inhibitors
medicine.disease_cause
Replication fork protection
03 medical and health sciences
0302 clinical medicine
Neoplasms
Genetics
medicine
Humans
DNA Breaks, Double-Stranded
Survey and Summary
Gene
030304 developmental biology
BRCA2 Protein
0303 health sciences
Mutation
BRCA1 Protein
DNA Replication Fork
Phenotype
Double Strand Break Repair
030220 oncology & carcinogenesis
Cancer research
Cisplatin
Subjects
Details
- Language :
- English
- ISSN :
- 13624962 and 03051048
- Volume :
- 49
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Nucleic Acids Research
- Accession number :
- edsair.doi.dedup.....acac6de62b34c8ee24b55b314e9f9b00
- Full Text :
- https://doi.org/10.1093/nar/gkab151