Brca1-Mediated Suppression Of Retrotransposon Activity - Resubmission - 1

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Project summary LINE-1/L1 retrotransposon is the only autonomous non-homologous retrotransposon active in the human genome. In the human genome, >100 copies of L1 are still able to move, in settings in which cellular defense mechanisms that repress retrotransposons are “breached”. Increasing evidence underscores the potential role of L1 protein expression and L1 activity in normal processes such as aging as well as in disease contexts like cancer initiation and progression. Genome instability is a key feature of many cancers and is increasingly considered not only a consequence of tumor development but a founding event for establishment and progression of cancer. Our recent work reveals that the combination of LINE-1 overexpression and BRCA1 knockdown leads to a novel form of genome instability we refer to as chromosome shattering. LINE-1, with its endonuclease and reverse transcriptase activity and its ability to “jump” within the genome increasing its copy number, is involved in chromatin instability at multiple levels. A whole genome screen aimed to identify factors that repress or support L1 movement (retrotransposition) established the tumor suppressor BRCA1 and the homologous recombination (HR) repair and Fanconi anemia pathways as potent inhibitors of L1 retrotransposition. The BRCA1 (BReast CAncer 1) gene is a well-established tumor suppressor the mutation or depletion of which is the cause of many breast, ovarian and other human cancers. The BRCA1 protein is a key player in the HR-based DNA repair pathway, a high fidelity repair process implemented by the cell during DNA replication to seamlessly correct and repair possibly deleterious damages. BRCA1 functions as a gatekeeper of genome integrity, an activity that has been extensively linked to cancer. BRCA1 has also been implicated in other molecular mechanisms such as chromatin remodeling, transcriptional control and translation regulation. Here we propose to explore the molecular mechanisms mediating BRCA1 suppression of L1 activity. Genetic, microscopy and biochemical approaches will be implemented to dissect functional interactions between BRCA1 and L1 retrotransposition. The identification of the basic mechanisms of BRCA1-mediated L1 suppression not only promises to clarify poorly understood facets of the L1 life-cycle but is also essential step to interpret L1’s role in the many cancers characterized by BRCA1 depletion.