Ricerc@Sapienza

Replication stress and cancer are induced by replication challenging sequences. On these regions the replisome cannot proceed efficiently, the forks stall inducing ss DNA and ds breaks. Telomeres are paradigmatic replication challenging sequences due to the repetitive nature of their sequence, the presence of a capping complex, and the tridimensional organization including G quadruplex pairing. The nuclear envelope contributes to telomere integrity and mutations of lamins, which alter the nuclear envelope, cause telomere dysfunction. We identified a mammalian telomeric protein, AKTIP, involved in telomere replication. Beyond working at telomeres, AKTIP displays a second relevant property: it is a lamin binding partner.
Although many evidence link genome and telomere integrity to the nuclear envelope, the mechanics of this interaction is not yet defined. AKTIP is the first characterized human protein locating at the nuclear envelope involved in telomere replication. This induces to hypothesize that the study of complexes involving AKTIP will give insights into replicative mechanisms at telomeres, into their control by the nuclear envelope, and information on replication stress and tumorigenesis. In particular the proposed experiment are aimed to define the mechanics of AKTIP in replication, to identify factors controlling replication at the nuclear envelope and to get insights into the role of the mouse orthologue of AKTIP, Ft1, in replication and tumorigenesis. Our data, besides clarifying AKTIP role in telomere replication and unraveling the function of factors acting in the same process, will give insights into the implication of nuclear envelope and telomere defects in genome instability and tumorigenesis, as independent and combined insults. This study will provide relevant results contributing to elucidating the molecular drivers linking replication stress and cancer and identifying in this way, putative therapeutic targets.