RRC ID 45590
著者 Lawrence KS, Chau T, Engebrecht J.
タイトル DNA damage response and spindle assembly checkpoint function throughout the cell cycle to ensure genomic integrity.
ジャーナル PLoS Genet
Abstract Errors in replication or segregation lead to DNA damage, mutations, and aneuploidies. Consequently, cells monitor these events and delay progression through the cell cycle so repair precedes division. The DNA damage response (DDR), which monitors DNA integrity, and the spindle assembly checkpoint (SAC), which responds to defects in spindle attachment/tension during metaphase of mitosis and meiosis, are critical for preventing genome instability. Here we show that the DDR and SAC function together throughout the cell cycle to ensure genome integrity in C. elegans germ cells. Metaphase defects result in enrichment of SAC and DDR components to chromatin, and both SAC and DDR are required for metaphase delays. During persistent metaphase arrest following establishment of bi-oriented chromosomes, stability of the metaphase plate is compromised in the absence of DDR kinases ATR or CHK1 or SAC components, MAD1/MAD2, suggesting SAC functions in metaphase beyond its interactions with APC activator CDC20. In response to DNA damage, MAD2 and the histone variant CENPA become enriched at the nuclear periphery in a DDR-dependent manner. Further, depletion of either MAD1 or CENPA results in loss of peripherally associated damaged DNA. In contrast to a SAC-insensitive CDC20 mutant, germ cells deficient for SAC or CENPA cannot efficiently repair DNA damage, suggesting that SAC mediates DNA repair through CENPA interactions with the nuclear periphery. We also show that replication perturbations result in relocalization of MAD1/MAD2 in human cells, suggesting that the role of SAC in DNA repair is conserved.
巻・号 11(4)
ページ e1005150
公開日 2015-4-1
DOI 10.1371/journal.pgen.1005150
PII PGENETICS-D-14-02988
PMID 25898113
PMC PMC4405263
MeSH Animals Autoantigens / genetics Caenorhabditis elegans / genetics Centromere Protein A Chromatin / genetics Chromosomal Proteins, Non-Histone / genetics Chromosomes / genetics DNA Damage / genetics* DNA Repair / genetics Genomic Instability / genetics* Humans M Phase Cell Cycle Checkpoints / genetics* Mad2 Proteins / genetics* Metaphase / genetics
IF 5.175
引用数 25
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm853 tm3039