APRIN(PDS5B) et PALB2, deux protéines impliquées dans la réparation de l'ADN par recombinaison homologue et l'apparition de cancers
|Abstract:||Cancer is the leading cause of death in Canada (30% of all deaths). By 2015, it was estimated that 78,000 Canadians would die of cancer. Moreover, 196,900 new cases of cancer were discovered in that same year (Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2015. Toronto, ON: Canadian Cancer Society; 2015). Each day, genome integrity is threatened by environmental conditions that can induce DNA damages (UV, chemicals, etc.). Amongst different types of lesions, double-strand breaks (DSB) are one of the most deleterious and can lead to cancer development. DSB can be repaired following two different and major pathways: Non-Homologous End-Joining (NHEJ) and Homologous Recombination (HR). HR mainly takes place during S/G2 phases and uses the intact sister chromatid as a template for repair. This renders HR to be a faithful mechanism, which depends on three important proteins: RAD51, PALB2 and BRCA2. The last two proteins are frequently found mutated in both breast and ovarian cancers. Understanding how each HR actor is specifically implicated in this pathway is important to develop strategies to fight cancer and constitutes the general aim of this thesis. In 2012, APRIN (Androgen-induced PRoliferation INhibitor), known as a regulator of the cohesin complex, was described as a new interacting partner of BRCA2 and an actor of HR. Nevertheless, how APRIN was specifically implicated in HR remained unclear. Hence, the major objective of this thesis was to functionally characterize APRIN in HR. We show that APRIN possesses a specific and independent role from the cohesin complex in HR and could be implicated in different steps during this repair pathway. Interestingly, APRIN expression levels in ovarian cancer tumours may be used as a prognostic marker. Moreover, to achieve the general objective of this thesis, we focused on another BRCA2 partner : PALB2. We studied the impact of different truncating mutations found in cancers on PALB2 functions. Surprisingly, we discovered that the consequence of an aggressive cancer-causing mutation could stem from an aberrant localization of PALB2. Consequently, this thesis provides important new information on the repair of DSB by HR and on the occurrence of cancers.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||24 April 2018|
|Collection:||Thèses et mémoires|
All documents in CorpusUL are protected by Copyright Act of Canada.