View/Open - Università degli Studi di Milano-Bicocca

Introduction
short telomeres [56,126,138–140]. More than its nuclease activity, the
structural integrity of MRX is important for telomere length maintenance in
cycling cells [141]. Only in cells arrested in G2/M, the nuclease activity of
Mre11 is required for telomere addition, suggesting a cell cycle-specific role of
MRX at telomeres [70].
MRX seems to have also an protective role at telomeres, as it inhibits
generation of telomeric ssDNA in cells lacking Ku [131] and cdc13-1 mutant
[142]. Mammalian MRN physically interacts with TRF2 and is recruited to
normal telomeres [143]. Also in shelterin lacking cells, MRN is recruited to
dysfunctional telomeres [144] and is required to remove the 3’ telomeric
overhang to promote chromosome fusions. MRN is also required to protect
newly replicated leading strand telomeres from NHEJ [145,146] (for a review
see [147]). Yeast RPA is also involved in telomere length regulation. Rfa2p
binds to telomeres and is enriched at telomeres in S phase. rfa2 mutant has
short telomeres due to reduced recruitment of Est1p, but not of Est2p and
Cdc13p, at telomeres [148].
Tel1 kinase is also involved in telomere maintenance. Like Ku, MRX and Tel1
are also involved in nuclear retention of TLC1 RNA [128]. Cells lacking TEL1
have short but stable telomeres due to reduced Est1p and Est2 recruitment at
telomeres, possibly owing to defective nuclear retention of TLC1 RNA
[140,149]. Like at DSBs, telomeric Tel1 binding is also dependent on Xrs2 and
is required for the recruitment of telomerase at short telomeres thereby
leading to a preferential elongation of short telomeres [150,151]. The kinase
activity of Tel1 is important for its lengthening activity [152,153] and Tel1
mutants with increased kinase activity have longer telomeres [154], but
precise knowledge on telomeric Tel1 target is lacking [155]. In fission yeast,
Tel1 (ATM) and Rad3 (ATR) phosphorylate the telomere protein Ccq1 and
promote Ccq1 interaction with Est1 for telomere maintenance [156,157].
Mec1 is also involved in telomere maintenance, as mec1 mutants have short
telomeres [158] and cells lacking both TEL1 or MRX and MEC1 undergo
telomere shortening and exhibit senescence phenotypes characteristic of cells
lacking telomerase [139,158]. Cells lacking telomerase undergo Mrc1
dependent checkpoint activation [159,160]. In the survivors arising from
telomerase lacking cells or in cells lacking yKu, Mec1 binding to telomeres
increases [161]. Thus, In contrast to Tel1, Mec1 associates with short,
19