Mechanisms of preventing replication stress-associated ssDNA gaps induced by chemotherapy

Línea de investigación

Genome Instability and Cancer Predisposition.

Descripción

Chronic replication stress (RS) is a prominent feature of cancer cells, mainly due to their continuous proliferation. Interestingly, this feature provides a therapeutic vulnerability to treat tumors.

Replication in human cells is tightly regulated and requires the coordinated functions of hundreds of proteins during the S-phase of each cell cycle, one of which is the tumor suppressor BRCA2. BRCA2 stabilizes replication forks and preserves genome integrity through its established role in DNA repair by homologous recombination and through its role in replication-associated gaps suppression, a process for which many mechanistic details are still poorly defined.

Based on our recent publication (Vugic etal Nature Commun. 2023), we hypothesize that the mechanisms of gap suppression are differentially activated depending on whether the RS is induced by nucleotide depletion (ex: HU, aphidicolin) or blocking lesions (either interstrand crosslink-induced by MMC, platinum salts, or protein-DNA complexes such as PARP inhibitors). Moreover, these mechanisms may implicate different factors and distinct domains of BRCA2. Importantly, shedding light on these questions may lead to finding novel vulnerabilities for cancer treatment as gap suppression has been put forward as an underlying mechanism of chemotherapy resistance in BRCA1/2 deficient tumours.

Using cell biology tools such as cell lines expressing variants identified in breast cancer patients, biochemistry and proteomics screens, this project aims to shed light on this question.

Contacto

Aura Carreira Moreno.

Correo electrónico: acarreira@cbm.csic.es

Centro de Biología Molecular Severo Ochoa (CBM).

Número de plazas ofertadas: 1.