Fine tuning the level of the Cdc13 telomere-capping protein for maximal chromosome stability performance

Abstract

Chromosome stability relies on an adequate length and complete replication of telomeres, the physical ends of chromosomes. Telomeres are composed of short direct repeat DNA and the associated nucleoprotein complex is essential for providing end-stability. In addition, the so-called end-replication problem of the conventional replication requires that telomeres be elongated by a special mechanism which, in virtually all organisms, is based by a reverse transcriptase, called telomerase. Although, at the conceptual level, telomere functions are highly similar in most organisms, the telomeric nucleoprotein composition appears to diverge significantly, in particular if it is compared between mammalian and budding yeast cells. However, over the last years, the CST complex has emerged as a central hub for telomere replication in most systems. Composed of three proteins, it is related to the highly conserved replication protein A complex, and in all systems studied, it coordinates telomerase-based telomere elongation with lagging-strand DNA synthesis. In budding yeast, the Cdc13 protein of this complex also is essential for telomerase recruitment and this specialisation is accompanied by additional regulatory adaptations. Based on recent results obtained in yeast, here, we review these issues and present an updated telomere replication hypothesis. We speculate that the similarities between systems far outweigh the differences, once we detach ourselves from the historic descriptions of the mechanisms in the various organisms.

Adaptation in replicative senescence: a risky business

“…However, the global amount of ssDNA induced at restrictive temperature in cdc13-1 cells might exceed that found in cells with two DSBs (Garvik et al 1995;Westmoreland et al 2018), suggesting that the nature of the damage, and not only the amount of exposed ssDNA, might be important for adaptation. Besides, the cdc13-1-induced telomere dysfunction at higher temperature also involves more complex molecular mechanisms, such as defective nuclear homeostasis of Cdc13-1 proteins and confounding temperature-dependent defect of the telomeres themselves (Paschini et al 2012;Mersaoui and Wellinger 2018), reinforcing the idea that the molecular nature of the damage might impact on adaptation efficiency. Other types of damage, induced by specific treatments, have also been used in vertebrate systems and suggest that adaptation operates only within a range DNA damage load (Yoo et al 2004;Syljuasen et al 2006;Rezacova et al 2011;Kubara et al 2012).…”

Telomere length regulation by Rif1 protein from Hansenula polymorpha

“…The single-stranded region of telomeres (3'-overhang) is bound and protected by the Cdc13 protein (Garvik et al, 1995;Lin and Zakian, 1996;Nugent et al, 1996) together with its partners Stn1 and Ten1 (the CST complex) (Grandin, 2001;Grandin et al, 1997;Mersaoui and Wellinger, 2019;Wellinger and Zakian, 2012). Cdc13 is a central hub for telomeric DNA synthesis as it mediates the main pathway of telomerase recruitment (synthesis of the G-strand), as well as assists in loading of the Pol𝛂 (synthesis of the C-strand) (Qi and Zakian, 2000;Wellinger and Zakian, 2012).…”

Loss of Cdc13 causes genome instability by a deficiency in replication-dependent telomere capping

“…CST has functional and structural similarity with the heterotrimeric replication protein A (RPA) and thus has also been dubbed t-RPA (telomeric RPA; [24]). Cdc13 as part of the CST complex facilitates telomere functions via several mechanisms: by facilitating telomerase-mediated telomere elongation [25,26], by assisting in telomere processing after replication [3], and by "capping" the telomere [1,27,28]. "Capping" is a term that encompasses at least two functions: a putative post-replication capping function where CST binds to the 3' ssDNA TG overhang and blocks degradation, and a DNA replication-dependent function where Cdc13 facilitates semi-conservative DNA replication through its interaction with the lagging strand machinery (even independent of telomerase extension [29,30]).…”