Mechanism and consequences of SLX4IP- and ERCC1-XPF-dependent telomere dysfunction

Somatic cells have finite replicative lifespans because telomeres undergo progressive shortening after DNA replication, which can lead to genome instability and induce senescence. Telomere dysfunction has profound physiological consequences and promotes the accelerated development of many age-associated pathologies such as tumorigenesis and kidney disease. We have previously described the adapter protein SLX4IP as an important regulator of recombination-based Alternative Lengthening of Telomeres (ALT), which is a telomerase-independent telomere maintenance mechanism. Intriguingly, SLX4IP interacts with the heterodimeric structure-specific endonuclease ERCC1-XPF, which cleaves the 3′ flaps of DNA intermediates that occur during several DNA repair pathways and also as a consequence of telomere maintenance. The physiological importance of ERCC1-XPF is underscored by the fact that inactivating mutations in XPF are associated with several genome instability syndromes. In addition, ERCC1-XPF is essential for kidney homeostasis and its loss leads to glomerular aging and renal fibrosis. To date, it remains entirely unclear why and how SLX4IP interacts with ERCC1-XPF and how this interaction relates to the cellular and physiological functions of this endonuclease. The objectives of this research proposal are, thus, to understand how SLX4IP regulates ERCC1-XPF function to ensure telomere stability and to elucidate the physiological consequences of a dysfunctional SLX4IP-ERCC1-XPF module. Specifically, we propose to characterize the molecular relationship of SLX4IP and ERCC1-XPF, to investigate how SLX4IP modulates ERCC1-XPF telomere functions, and to understand the consequences of a dysfunctional SLX4IP-ERCC1-XPF module on general genome maintenance and on organ homeostasis using mouse kidney fibrosis as model system.