Exploring the connection between YY1 and telomere biology

Abstract

Telomere length becomes progressively shorter with age causing senescence and apoptosis of somatic cells. To overcome the problem of telomere shortening, cancer cells either activate telomerase or induce Alternative Lengthening of Telomeres (ALT), a homologous recombination-based pathway. SLX4IP was identified as a key regulator of the ALT pathway, and loss of SLX4IP increases ALT-related phenotypes. A synthetic lethality screen conducted for SLX4IP in U2OS cells identified YY1 as a top hit, which was later confirmed via an siRNA screen. YY1 is a multifunctional transcription factor with roles in many biological processes. It can function as an activator or a represser in a context dependant manner. It also has roles in chromatin remodelling and genome organisation. Protemic datasets have identified YY1 as an interactor with the Shelterin complex and with the ALT factor RAD51AP1. Previous Co- IP experiments performed in the lab have shown YY1 to be an interactor of RAP1 and hypothesizing on the study conducted by Robinson et al., a potentially sumoylated form of RAP1. These observations pose the question about the potential role of YY1 in telomere maintenance. This study addresses the colocalisation of YY1 with the telomeres. By using a CRISPR/Cas9 based condtional YY1 knockout cell line and an inducible GFP-YY1 cell line, the effect of YY1 loss and overexpression have been studied on the telomeres by monitoring the changes in telomere length, fragility and dysfunction.