ATR contributes to telomere maintenance in human cells.
Telomere maintenance is essential to preserve genomic stability and involves several telomere-specific proteins as well as DNA replication and repair proteins. The kinase ATR, which has a crucial function in maintaining genome integrity from yeast to human, has been shown to be involved in telomere maintenance in several eukaryotic organisms, including yeast, Arabidopsis and Drosophila. However, its role in telomere maintenance in mammals remains poorly explored. Here, we report by using telomere-fluorescence in situ hybridization (Telo-FISH) on metaphase chromosomes that ATR deficiency causes telomere instability both in primary human fibroblasts from Seckel syndrome patients and in HeLa cells. The telomere aberrations resulting from ATR deficiency (i.e. sister telomere fusions and chromatid-type telomere aberrations) are mainly generated during and/or after telomere replication, and involve both leading and lagging strand telomeres as shown by chromosome orientation-FISH (CO-FISH). Moreover, we show that ATR deficiency strongly sensitizes cells to the G-quadruplex ligand 360A, enhancing sister telomere fusions and chromatid-type telomere aberrations involving specifically the lagging strand telomeres. Altogether, these data reveal that ATR plays a critical role in telomere maintenance during and/or after telomere replication in human cells.
CEA/DSV/iRCM/SCSR, Laboratoire de Radiopathologie, INSERM-Université Paris VII U967, 92265 Fontenay-aux-Roses, France.
Gaëlle
G
Pennarun
Françoise
F
Hoffschir
Deborah
D
Revaud
Christine
C
Granotier
Laurent R
LR
Gauthier
Patrick
P
Mailliet
Denis S
DS
Biard
François D
FD
Boussin
D000293:Adolescent; D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D005260:Female; D005347:Fibroblasts / Q000737:chemistry; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D016615:Telomere / Q000737:chemistry* / Q000187:drug effects
C502660:2,6-N,N'-methyl-quinolinio-3-yl-pyridine dicarboxamide; D018797:Cell Cycle Proteins; D011725:Pyridines; D011804:Quinolines; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases