View/Open - Università degli Studi di Milano-Bicocca

Introduction
The Replication Protein A (RPA) heterotrimeric complex is the major singlestranded
DNA-binding complex in eukaryotic cells. RPA can bind with high
affinity to single-stranded DNA all over the genome and has multiple roles
during DNA replication, repair, and recombination [40]. RPA has multiple
oligosaccharide/oligonucleotide binding (OB) folds, distributed among all three
subunits, which are used for both DNA and protein recognition [41]. In
budding yeast, Cdc13 is structurally similar to Rpa1, whereas Stn1 and Ten1
are structurally similar to Rpa2 and Rpa3 subunits of the RPA complex. Thus, it
was proposed Cdc13, Stn1 and Ten1 function as a telomere-specific RPA-like
complex [28,42].
In the hypotrichous ciliate Oxytricha nova, an α-β protein heterodimer binds
specifically to telomeric single-strand DNA and protects telomeres [43,44].
Fission yeast Pot1 (Protection of Telomeres) is the structural homolog of
budding yeast Cdc13. OB folds are present in α-β proteins of Oxytricha nova
and also in fission yeast and human Pot1 [45]. Fission yeast POT1 null cells
undergo nucleolytic degradation of telomeres and lose telomeres within one
cell cycle [46]. In mouse, two Pot1 orthologs exist namely Pot1a and Pot1b.
Pot1a protects telomeres from uncontrolled resection and DNA damage repair
activities which are detrimental to normal telomeres [47]. Similarly human
hPot1 can bind and protect telomeric ssDNA and regulate telomere length
[45,48].
Recently, CST homologs were also identified in plants and in mammals.
Arabidopsis plants lacking At-STN1 display developmental defects and reduced
fertility and these phenotypes are accompanied by catastrophic loss of
telomeric and subtelomeric DNA, high levels of end-to-end chromosome
fusions, increased G-overhang signals, and elevated telomere recombination
[49]. Xenopus laevis xCST protein complex is involved in priming DNA synthesis
on single-stranded DNA template for replication [50]. Depletion of human
CTC1 by RNAi triggers a DNA damage response, chromatin bridges, increased
telomeric G overhangs, and sporadic telomere loss [51]. Similarly STN1
knockdown cells have increased telomeric G overhangs [52,53].
A recent study found that mutations in CTC1 cause a rare human genetic
disorder called “Coats plus”, characterized by neurological and gastrointestinal
defects. Patients suffering coats plus have shortened telomeres with
spontaneous γH2AX-positive cells in cell lines indicative of DNA damage
8