DNA Damage Response and Spindle Assembly Checkpoint Function throughout the Cell Cycle to Ensure Genomic Integrity

Katherine S. Lawrence, Thinh Chau, JoAnne A. Engebrecht

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005150
JournalPLoS Genetics
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2015

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M Phase Cell Cycle Checkpoints
DNA damage
DNA Damage
cell cycle
genomics
Cell Cycle
metaphase
DNA
Metaphase
damage
repair
DNA repair
Germ Cells
DNA Repair
germ cells
germ cell
Ensure
defect
genome
Chromosomal Instability

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

DNA Damage Response and Spindle Assembly Checkpoint Function throughout the Cell Cycle to Ensure Genomic Integrity. / Lawrence, Katherine S.; Chau, Thinh; Engebrecht, JoAnne A.

In: PLoS Genetics, Vol. 11, No. 4, e1005150, 01.04.2015.

Research output: Contribution to journalArticle

Lawrence, Katherine S. ; Chau, Thinh ; Engebrecht, JoAnne A. / DNA Damage Response and Spindle Assembly Checkpoint Function throughout the Cell Cycle to Ensure Genomic Integrity. In: PLoS Genetics. 2015 ; Vol. 11, No. 4.
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