Shaping the BRCAness mutational landscape by alternative double-strand break repair, replication stress and mitotic aberrancies

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.

Sister chromatid exchanges induced by perturbed replication are formed independently of homologous recombination factors

“…Such allelic deletions have been reported previously at common-fragile sites (Durkin and Glover, 2007). Moreover, the observed submicroscopic deletions that span CFS regions were shown to be flanked by microhomology regions, suggesting the involvement of POLQ-mediated end joining, consistent with the mutational signatures observed in BRCA1/2-deficient tumors (Glover et al, 2017; Stok et al, 2021). Moreover, a role for POLQ in the mitotic processing of stalled replication forks in BRCA-deficient cells fits well with the synthetic lethality between BRCA2 and POLQ, as previously described (Ceccaldi et al, 2015; Mateos-Gomez et al, 2015; Mengwasser et al, 2019).…”

RAD52: Paradigm of Synthetic Lethality and New Developments

“…It is known that BRCA1 and BRCA2 play important roles in HR-dependent repair of DSBs. However, BRCA-deficient tumors show increased dependence on alternative pathways such as SSA and a-EJ to overcome their “BRCAness” phenotype, characterized by reduced DSB repair, impaired replication fork protection, and hypersensitivity to DNA damaging agents ( Stok et al, 2021 ). Through its strand annealing and DNA pairing activities, RAD52 is central to the SSA and BIR pathways ( Gottifredi and Wiesmuller 2020 ).…”

When breaks get hot: inflammatory signaling in BRCA1/2-mutant cancers

“…Defective HR yields aberrant genomes that are enriched for several mutational signatures, including base substitution signatures (SBS3, SBS8), indel signatures (ID6, ID8), and rearrangement signatures (RS1, RS3, and RS5) [3,[24][25][26]. These genomic alterations can be explained by the usage of alternative, nonconservative DNA repair mechanisms to repair DNA DSBs (Figure 1C) [3,27]. In particular, the usage of non-homologous end-joining, polymerase Theta (POLQ)-mediated end-joining (also referred to as alternative end-joining), or single-strand annealing leads to deletions and translocations that are characteristic of HR-deficient cancers [3,24,25,28,29].…”