Role of POT1 in telomere length regulation

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Project Summary We will use state-of-the-art biochemical, cellular and genetic approaches to understand mechanistically how ssDNA binding proteins protect telomeres from activating a DNA damage response, regulate its length and replication. Using novel in vitro biochemical assays, we will examine whether the molecular distinctions between RPA and hPOT1 underlie their unique functions at telomeres. We will define the residues in hPOT1 that are required to repress telomere end protection and C-strand resection (Aim 1). We will determine mechanistically how POT1b promotes telomere length maintenance, and use hematopoietic stem cells conditionally depleted of endogenous POT1a/b to define the amino acid residues involved in telomere elongation necessary for the stem cell maintenance (Aim 2). We will explore how POT1a protects telomeres from replication stress. Finally, we used BioID to identify Claspin as a telomere interacting protein involved in DNA replication at telomeres devoid of POT1a (Aim 3). The proposed studies present a unique opportunity to address some of the most important questions in the telomere field.