TY - JOUR
T1 - The presence of extra chromosomes leads to genomic instability
AU - Passerini, Verena
AU - Ozeri-Galai, Efrat
AU - De Pagter, Mirjam S.
AU - Donnelly, Neysan
AU - Schmalbrock, Sarah
AU - Kloosterman, Wigard P.
AU - Kerem, Batsheva
AU - Storchová, Zuzana
PY - 2016/2/15
Y1 - 2016/2/15
N2 - Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis.
AB - Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis.
UR - http://www.scopus.com/inward/record.url?scp=84958206574&partnerID=8YFLogxK
U2 - 10.1038/ncomms10754
DO - 10.1038/ncomms10754
M3 - Article
C2 - 26876972
AN - SCOPUS:84958206574
SN - 2041-1723
VL - 7
JO - Nature Communications [E]
JF - Nature Communications [E]
M1 - 10754
ER -