Cell biology of disease Telomeropathies : An emerging spectrum disorder

Correspondence to Jerry W. Shay: Jerry.Shay@utsouthwestern.edu Abbreviations used in this paper: AML, acute myelogenous leukemia; DKC, dyskeratosis congenita; HHS, Hoyeraal-Hreidersson syndrome; HSC, hematopoietic stem cell; IPF, idiopathic pulmonary fibrosis; POT1, protection of telomeres 1; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TIF, telomere-induced foci; TIN2, TRF1-interacting nuclear protein 2; TPP1, TIN2interacting protein 1; TRF, telomere repeat–binding factor. Introduction Human telomeres are composed of thousands of hexameric TTAGGG nucleotide repeats and the protein components that bind to and associate with them, including the shelterin complex (de Lange, 2010). These proteins recruit DNA repair factors to the telomeres and modify them so they mask rather than stimulate DNA repair. Thus, shelterin proteins protect telomeres from being recognized as DNA double-strand breaks. In the absence of such protection, catastrophic chromosome fusions occur (Sfeir and de Lange, 2012). Because of the “end replication” lagging strand synthesis problem and certain less-well defined end replication– processing events, telomeres shorten by 50–100 base pairs per cell division in vitro (Levy et al., 1992; Wu et al., 2012) and 20–30 base pairs per year in peripheral blood mononuclear cells during adulthood, which is modifiable by environmental factors (Daniali et al., 2013). This progressive shortening eventually interferes with the telomeres’ ability to suppress the DNA damage recognition machinery, triggering telomere-induced foci (TIFs) that lead to a p53/p21-mediated cell growth arrest called replicative senescence (Chin et al., 1999; Takai et al., 2003). Proliferating germline and certain adult somatic transit-amplifying stem-like cells express telomerase, a ribonucleoprotein reverse transcription; in general this telomerase activity only slows down the rate of progressive telomere shortening. The catalytic component of telomerase, TERT (telomerase reverse transcriptase), utilizes the telomerase RNA component (TERC) as a template to add new telomere repeats to the ends of existing telomeres in order to maintain telomere integrity (Wright et al., 1996). Telomere maintenance requires TERT, TERC, and a number of other gene products required for telomerase assembly and recruitment, as well as gene products necessary for the correct protection of the telomeres and processing before telomerase activity (Fig. 1; Palm and de Lange, 2008). Defects in these genes cause a spectrum of disorders leading to proliferative failure of a variety of tissues (Dokal, 2011). New syndromes characterized by impaired telomere maintenance, referred to as “telomeropathies,” “telomere disorders,” or “telomere syndromes” are increasingly being identified. Telomere length measurement or telomere dysfunction (measured by colocalization of shelterin components and DNA damage signals) are often used to identify a disorder of telomere maintenance in the laboratory (Touzot et al., 2010; Anderson et al., 2012; Ballew et al., 2013), whereas in the clinic telomeres are measured generally by flow cytometry or fluorescent in situ hybridization (FISH). This review focuses on the causes and symptoms of these syndromes with an emphasis on mutations recently linked to disorders of telomere biology. We also present a number of diseases not previously considered telomeropathies that have recently been shown to be related to telomere biology. Lastly, we discuss several models that may explain the heterogeneity of tissue failure in these disorders.